Category Archives: Lymphomas, Leukemias, Myelomas

Hematologic cancers that derive from B cells, T cells, myeloid cells and others. Important tumor class.

Updates from #CowenHealthCare 2020 – CAR T and it’s competitors

March 3, 2020Aleta Biotherapeutics, ALL, AML, B cell lymphoma, B cell lymphomas, biologics, BITE bi-specific, cancer, CAR T, CAR T cells, Chimeric Antigen Receptor, chimeric antigen receptors, CNS pathologies, immunotherapy, leukemia, lymphoblastic leukemia, lymphoma, Lymphomas, Leukemias, Myelomas, myelofibrosisAML, CAR T cells, cell therapy, leukemia, lymphoma, myelomaPaul Rennert

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If you work in cell therapy you have follow all kinds of therapeutic developments in indications of interest which for us at Aleta Biotherapeutics (www.aletabio.com) includes specific solid tumor indications, and several hematologic malignancies.

Over the last few days we’ve gotten interesting updates regarding diverse hematologic malignancies, including news about therapeutics for front line (newly treated) or relapsed or refractory (r/r) Non-Hodgkin Lymphoma (NHL), multiple myeloma (MM) and acute myeloid leukemia (AML) patients and the myelodysplastic syndromes (MDS). Note here that the reference to different lines of therapy – front line or early line vs r/r, because the treatment paradigms change as patients fail earlier lines of therapy, ie. as they become refractory to or relapse from their current therapy. This can become a long and arduous battle for patients who repeatedly fail treatment. Unfortunately, this is often the case in r/r MM, r/r AML and MDS and in some subtypes of r/r NHL.

On Monday (2 March 2020) I attended the “Cell Therapy & Myeloma” panel at the 40^th Annual Cowen Heath Care Conference. This panel covered much more than the title implies, and I really liked the format which is built on the back of questions posed to the audience, to an (unnamed) group of specialists in the field who were polled in advance, and to the seated key opinion leaders (KOLs), in this case Dr Deepu Madduri (Mt Sinai) and Dr Jacob Soumerai (MGH).

They covered a lot of ground.

The first series of questions sought to pin down trends in r/r Follicular lymphoma (FL) a subtype of NHL that can become difficult to treat if patients fail successive lines of treatment. The Leukemia Lymphoma Society has a primer here –https://lymphoma.org/aboutlymphoma/nhl/fl/relapsedfl/. There has been brisk drug development in r/r NHL including FL. Novel drug classes include CAR-CD19 T cells, bispecific T cell engagers, small molecule drugs (targeting PI3K, Bcl2, BTK, EZH2) and new antibodies. The Cowen panel worked through a series of questions regarding this landscape and there were several key takeaways.

One was the clear preference, by the anonymously polled specialists and by the seated panelists, for CAR-CD19 therapy as the most exciting new drug for r/r FL. The driver here is the durability of response (DOR) in really late line patients and the sense that both overall response rate (ORR) and DOR will only improve as these cell therapeutics move to earlier lines of therapy. It was striking that several classes of bispecific antibodies (the CD3 x CD20 and CD3 x CD19 bispecifics) elicited strong enthusiasm from the audience (mostly analysts and investors) but only muted enthusiasm from the KOLs. This lack of enthusiasm had 2 distinct bases: 1) limited data to date, and 2) “I can give a bispecific after I give a CAR T, but not the other way around”, which was a very interesting thought (and given despite of the few case reports of CD3 x CD20 bispecific therapy working in several relapsed CAR-T patients). I think that in later line patients these clinicians want to keep their options open as long as possible.

Among the other classes of therapeutics, Epizyme’s EZH2 inhibitor tazemetostat received significant support based on the ability to select EZH2-mutated patients, and on good DOR and on good tolerability, the latter thought to be better than the PI3Kdelta class inhibitors, BTK inhibitors or BCl2 inhibition. The consensus was that tazemetostat could see up to 20% market penetration in third line FL after the expected launch in June 2020.

Among the PI3Kdelta inhibitors, Bayer’s copanlisib was singled out as best-in-class with little differentiation among the others (from Gilead, Verastem, MEI, Incyte, or TG Therapeutics). Finally, in this setting of r/r FL, both venetoclax (a Bcl2-inhibitor) and polatuzumab vedotin (a CD79b antibody-drug conjugate), were relegated to minor use by the specialists and panelists.

The uptake of CAR-CD19 therapies has been brisk, and the panelists highlighted quicker payor approvals and the accelerating pace of referrals to cell therapy centers. The consensus is for 30% increase in patient number treated in 2020 (so roughly 1350 patients in the US, vs 1050 treated last year).

The discussion stayed on CAR-CD19 therapeutics to touch on some of the newer trials and entrants. Kite/Gilead is running a Phase III trial of axi-cel (axicabtagene ciloleucel, brand name Yescarta) in second line DLBCL patients vs a standard of care regimen of high dose chemotherapy followed by an autologous stem cell transplant. Data are anticipated in the second half of 2020. The Cowen moderators passed the question: will this trial show a progression free survival (PSF) benefit? Mind you, this is a low bar since overall survival – the shining triumph of cell therapy – is not part of the question. The audience (again, mainly investors and analysts) was overwhelming positive, giving about 70% odds of a positive impact on PFS. Here the panelists agreed, citing the fact that this trial was enrolling high-risk patients and therefore the comparator arm of the trial (chemo + ASCT) should do very poorly. Success with this trial would move axi-cel up a line of therapy (from 3^rd or later to 2^nd or later) and bolster the health care value argument that patients may avoid ASCT altogether. We are apparently already seeing this effect, as a talk at #TCMT20 highlighted the steep decline in transplants being done in DLBCL.

Sticking with axi-cel, this CAR-CD19 cell therapy was highlighted as the one most likely to be the market leader by 2023, based on the (currently) much shorter manufacturing and turnaround time as compared to tisa-cel (tisagenlecleucel from Novartis, brand name Kymriah). The panelists agreed with the specialist poll, despite the fact that they also felt that tisa-cel may be better tolerated by patients overall. Further, the panelists did note that the difference in manufacturing turnaround was likely to diminish as Novartis improves its product workflow. So we’ll have to wait and see.

Competition may also play a role. The long-awaited Juno > Celgene > BristolMyers Squibb CAR-CD19 liso-cel (lisocabtagene maraleucel) should see its first approval soon, and several allogeneic and non-T cell based programs are advancing. Cowen’s moderators highlighted a number of these for discussion. Allogene CAR-CD19, called ALLO-501 is currently in a Phase 1 trial enrolling r/r diffuse large B cell lymphoma (DLBCL) and r/r FL patients, with initial data expected later this year. The moderators put forward the question: what percent of (responding) patients have to show a durable response for this to be an exciting option to the autologous CAR-CD19 products. It’s a complex question since the current approved CAR-CD19s show about a 50% durable response rate within the responders, where a goodly proportion of the patients that do not have a durable response are relapsing after a response, sometimes with CD19-negative lymphoma or leukemia (ie. the cancer has undergone natural selection and loses target antigen expression). The polled specialists and the panelists wanted to see a pretty high durable response rate, 35-40% (specialists) up to 50% (the panelists). If the field were to see responses as good as axi-cel, tisa-cel and liso-cel, this would be “a huge advance”, according to Dr Soumerai of MGH.

Of note, Allogene itself was a bit more cautious at their public company presentation later in the day. Dr David Chang, Allogene’s CEO, provided some guidance and set expectations. He noted that the company would report early data form the ALLO-501 program at #ASCO20 and/or #EHA20 but stressed the readouts of safety and degree of lymphodepletion from up to 3 dose cohorts, and with several different doses of their lymphodepletion agent ALLO-647, and anti-CD52 antibody. In the ALLO-501 trial this is given along with the lymphodepeleting chemotherapy combination of cyclophosphamide and fludarabine (Cy-Flu). Among the other allogeneic and off-the-shelf CAR-CD19 programs several were highlighted either by the audience (Fate Therapeutics induced CAR-NKs) or the panelists (the Takeda/MD Anderson NK program). Other programs from Atara, CRISPR, and Precision all would have to show some or more data in order to get the specialists or the panelists to take notice.

Notably, there was consensus among the audience, polled specialists and panelists that CD3 x CD20 bispecifics would be less efficacious than CAR T cells, regardless of the specific therapeutics (eg. from Roche or Regeneron or Genmab). Further, Dr Madduri expressed concern at the need to keep dosing patients both because of inconvenience and possible safety over time. Her view is that patients prefer a single dose CAR.

Finally in the r/r DLBCL space, both polled specialists and the panelists saw minimal roles for the anti-CD79b-drug conjugate polatuzumab vedotin (brand name Polivy, from Roche) or the anti-CD19-ADCC competent antibody tafasitamab (from Morphosys, which now has a 30 August PDUFA date with FDA). Both of these biologics need to be given in combination with other therapeutics and there did not appear to be a benefit over standard combinations. More specifically, polatuzumab vedotin is given with rituximab and bendamustine and was considered “tolerable” but perhaps best used in a bridge to transplantation setting or a bridge to CAR-CD19 cell therapy. Tafasitamab was recently written up by Jabob Plieth here: https://www.evaluate.com/vantage/articles/analysis/why-2020-spotlight-will-fall-tafasitamab.

Turning to r/r MM there were a series of questions about lines of therapy and which were preferred. For newly diagnosed patients and for second-line patients the clearly favored standard of care was an ‘ImID’ (immunomodulatory agent, eg. revlimid) plus the anti-CD38 antibody daratumumab (brand name Darzalex, from Johnson & Johnson’s Janssen division) plus dexamethasone (aka triple therapy) with perhaps a proteasome inhibitor added (thus, a quad). The use of daratumumab in early line therapy will continue to grow as it is payor-approved for early-line use.

For later line therapy, the moderators first brought up selinexor (brand name Xpovio, from Karyopharm Therapeutics), a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE), which was granted accelerated approval last year for use in in combination with dexamethasone for adult r/r MM patients who received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two ImIDs, and an anti-CD38 monoclonal antibody. There was a consensus view that this drug will see flat to diminishing use due to poor tolerability. Dr Madduri noted that she gives this drug once week rather than twice a day (as labeled) in an effort to improve patient tolerance and only used it as a bridge to clinical trial enrollment (ie. on something else, for example, CAR-BCMA cellular therapy. Curiously there were no questions about isatuximab-irfc (brand name Sarclisa, from Sanofi-Aventis), newly approved in combination with pomalidomide and dexamethasone for adult patients with r/r/ MM and at least two prior therapies (see this SITC writeup: https://www.sitcancer.org/aboutsitc/press-releases/2020/isatuximab-irfc).

As for CAR T cells for multiple myeloma, the panelists were hesitant to pick a winner between the two advanced CAR-BCMA programs: bb2121 (Bluebird) and JNJ-4528 (from J&J, formally called LCAR-B38M) until J&J updated PFS data. At their public company presentation Nick Leschly, Bluebird’s CEO, noted that they will file the BLA for bb2121 (now called idecabtagene vicleucel or ide-cel) in the first half of this year, and would release longer-term follow-up data from the ide-cel clinical trials KarMMa and CRB-401 in the second half of the year. The BLA will be filed despite the “slow-down” from FDA necessitated by the agency’s request for additional lentivirus production characterization information from their chosen cell suspension manufacturing method (no details given). What the FDA has asked for apparently is both different from and more than the EU agency (EMA) wanted.

On the allogeneic CAR T cell front, Dr Chang at Allogene noted that they would have early data on ALLO-715 (their version of a CAR-BCMA therapy) at #ASH20. Here he noted they are considering dropping the Cy-Flu lymphodepletion and just using their anti-CD52 antibody to lymphodeplete, we’ll see (this doesn’t strike me as realistic).

In general both the polled specialists and the panelists were more enthusiastic about CAR-BCMA therapy than several other modalities, including belantamab mafodotin (from GSK), an antibody-drug conjugate, composed of an anti-BCMA monoclonal antibody bound to auristatin F. This drug was thought to be not quite good enough given the unmet need, there remain concerns about the ocular toxicity (the bane of ADC technology) and keen disappointment that the response rate dropped below 30% ORR in daratumumab-refractory patients. Clearly this therapeutic will see some use in late line therapy, and further clinical development has yielded results in earlier line as reported on 2 March (see https://www.evaluate.com/vantage/articles/news/trial-results/karyopharm-comes-boston-springtime). A similar wait-and-see approach is being taken by these specialists and panelists to the CD3 x BCMA bispecifics, which are currently viewed as best for community hospital settings without CAR T cell capacity or for patients who cannot wait for the cell therapy production.

One theme in r/r MM is the concern that patients are still not being cured, even with cell therapies. The gradual relapse from CAR-BCMA treatment that one sees in all the clinical studies has been linked either to CAR T persistence being limited or to diminished BCMA antigen expression on the cancer cells. Of course, these two things may be related. One desire expressed by Dr Madduri was for a CAR-BCMA therapy with better persistence properties.

Two short notes while we’re here. Gilead stated at their public company presentation during Cowen Health Care that the value driver for the Forty Seven acquisition was the MDS data (https://xconomy.com/san-francisco/2020/03/02/gilead-boosts-cancer-drug-pipeline-with-4-9b-deal-for-forty-seven/). And hematologic drug heavyweight venetoclax (the Bcl-2 inhibitor from Abbvie) scored a miss in an AML confirmatory trial (https//pharmaphorum.com/news/abbvie-roches-venclexta-fails-in-confirmatory-aml-trial/). In summary, a busy couple of days.

As many readers know, Aleta Biotherapeutics builds cellular therapeutics with exemplary persistence and fitness properties. We have two cell therapy programs heading for the clinic now. One will treat r/r AML patients both in the pediatric and adult patient populations. Our solid tumor program is designed to treat patients relapsing from breast or lung cancer with brain metastases. We also have a biologics program specifically created to ‘rescue’ CAR-CD19 T cells in patients relapsing from therapy. You can find out more at www.aletabio.com or email me at paul.rennert@aletabio.com or just call me at 1-508-282-6370 and of course follow me on Twitter @PDRennert and @BioAleta.

That’s it for now. Stay tuned.

CAR T updates – tangled tales unwound

March 20, 2016ALL, B cell lymphoma, CAR T cells, Chimeric Antigen Receptor, CLL, immunotherapy, leukemia, lymphoblastic leukemia, lymphoma, Lymphomas, Leukemias, Myelomas, myelomaPaul Rennert

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Last month we saw a biomedical media campaign go a bit off the rails. A press release from the American Association for the Advancement of Science (AAAS: see for example https://www.sciencenews.org/article/memory-cells-enhance-strategy-fighting-blood-cancers) and the Fred Hutchinson Cancer Center, was picked up by multiple media outlets who quickly spun the story of CAR-T-cell mediated rapid and complete clearance of B cell leukemias and some lymphomas from very ill patients and turned it into the “cancer cured” sort of headlines that serve as great click-bait but don’t do much to really educate the reader.

But what first caught my eye was an odd distortion of the data as presented in the session entitled “Fighting Cancer and Chronic Infections with T Cell Therapy: Promise and Progress” (see https://aaas.confex.com/aaas/2016/webprogram/Session12231.html). Several credible sources were telling very different stories about the progress presented. To take one example, BioWorld Today told the story of the clear benefit of using naive T cells as the recipient for cellular therapy, while FierceBiotech (and many other outlets) focused on the benefit of using memory T cells instead (see http://bit.ly/1UdLqDs). Indeed the claim was made that even a single memory T cell could affect a cure – which was not really the point, or an important conclusion of the presented works.

It follows that the pressers were used to talk up CAR T cell company stocks, which have been languishing along with the rest of biotech.

All of this came across as garbled and confusing. I found it all very frustrating.

So now I’ve gone through the abstracts presented at AAAS and some of the primary literature, and I’ve a Cliff Notes version of what data were actually presented and what the data mean and don’t mean. I seems clear that the confusion regarding the results arose from the oversimplified weaving of two talks (by Dirk Busch and by Steven Riddell) into one tangled “story”. Lets untangle the knot and follow the threads.

Riddell’s work is closely followed in the CAR T field – not surprising as Dr. Riddell, from the Fred Hutchinson Cancer Center in Seattle, is a technology leader and a cofounder of Juno Inc. The story presented at the AAAS symposium is interesting but perhaps more controversial than one might have gathered from the press reports. Some of the work was recently published (http://www.nature.com/leu/journal/v30/n2/full/leu2015247a.html). They start with the observation that in all reported CAR-19 clinical trials, patients have received back a random assortment of their (now CAR-transduced) T cells, meaning that the cell population is a collection of naive T cells, effector T cells and memory T cells representing both the CD4 and CD8 T cell lineages. This introduces a variable into therapy, as different patients are likely to have different percentages of these various T cell subsets. Indeed there is quite a list of variables that may impact the efficacy of CAR T cell treatment including baseline immune competence, prior treatments and antigen load. With this in mind Riddell and colleagues are trying to control the one variable that they can, which is the composition of the transduced T cells going into the patient. By analyzing CAR cell subsets for tumor cell killing function they arrive at the “most potent” combination of CD4+ T cells and CD8+ T cells and conclude that the findings will be important for the formulation of CAR T cells therapeutics for use in patients.

The data in the paper are derived from normal donor and cancer patient PBMC samples that are tested in vitro using cell culture assays and in vivo using humanized mice (NOD/SCID/yc-deficient mice; NSG) reconstituted with T cells and tumor target cells (Raji) that express CD19. The CAR T construct is a “generation 3” CAR having CD28, 41BB and CD3 signaling domains downstream of the well-studied FMC63-derived anti-CD19 scFv.

Some results:

– substantial differences were seen in the T cell populations between normal donors and cancer patients, with most patients having a higher percentage of CD8+ than CD4+ T cells.

– patient samples also contained more memory T cells than did normal donor samples. A further refinement to the memory T cell definition allows one to identify effector memory and central memory T cells. The latter are a long-sustained population of antigen-educated T cells that contribute to immunological memory, such as one retains after a vaccination against a virus for example.

– both CD4+ and CD8+ T cells were readily transduced with the CAR-19 construct, and when presented with target cells in vitro both cell types responded. CD8 T cells mediated target cell lysis more effectively than CD4+ T cells, but the latter proliferated more vigorously and produced more pro-inflammatory cytokines such as IFNy and IL-2.

– among the CD4+ subset, naive T cells (those not previously antigen-activated) produced more cytokines than the memory cell subsets. In vivo, naive T cells were more potent in controlling tumor growth than central memory T cells which were in turn more potent than effector memory cells.

– similar analyses of CD8+ cells revealed that, of the three subsets, central memory CD8+ T cells were the most potent in vivo, a result that was most closely associated with the enhanced proliferation and expansion of this subset.

– the activity of CD8+ central memory T cells was further enhanced by the addition of CD4+ T cells, notably those of the naive subset. This effect was seen using cells from normal donors and cells from B cell lymphoma patients (specifically, Non-Hodgkin Lymphoma (NHL) patients). The improved in vivo activity was due to enhanced proliferation and expansion of T cells in the NSG mouse model, specifically an increase in the peak of CD8+ cell expansion, in line with clinical results (see below). I’ll note as a reminder that all of the available clinical results are from CAR T cell populations that had not been sorted into naive and memory subsets. Also, many researchers in the field believe that naive T cells (CD4 and CD8) have the best proliferative capacity and potency.

Regardless, the Riddell work suggests a straightforward improvement in the ability to create more potent CAR T cell preparations for use in the clinical setting. There are some caveats however. In the in vitro and in vivo models used, antigen (CD19) is abundant, even in the NSG mouse, due to robust expression of rapidly dividing CD19+ Raji cells. As noted earlier, antigen availability may be an important limiting feature for some patients, and may be more important than the composition of the T cell subset tested. Fortunately the relative importance of these variables could easily be examined in vivo by using sub-optimal Raji cell numbers, or using transfected cells with different levels of CD19 expression, to vary the antigen load.

The Busch study at the same symposium was notable for dispensing with CD4+ T cells altogether and using just CD8+ central memory T cells to control CMV infection (that can occur following allogeneic hematopoietic stem cell transplantation). Nearly all of this work has been performed in mouse models, with a small number of patients treated under compassionate use protocols (see e.g. http://www.bloodjournal.org/content/124/4/628). In the mouse models very small numbers of antigen-specific memory T cells can expand to control viral infection, and this has been taken as evidence (in the popular press mainly) that similar technology could be applied in the CAR T setting. However, numerous studies have shown conclusively that very large-scale expansion is required to achieve optimal potency, to a degree that would seem beyond the capacity of a small number of cells or a single cell. Further, studies in acute lymphocytic leukemia patients presented by Carl June last fall at the Inaugural International Immunotherapy meeting in NY showed that clonal selection and perhaps competition was a component of successful therapy for some patients, a process that would be eliminated or reduced by using a limited cell number in preparing the CAR T cells. The Busch study makes the further argument that central memory CD8+ T cells themselves possess “stem-ness”, that is, they can give rise to functionally diverse CD8+ T cell lineages and as such should have no limit to their proliferative capabilities. While this was demonstrated convincingly in mouse models it would seem a difficult finding to translate to the CAR T setting, although the work may find utility in the adoptive cell transfer setting (e.g. of selected but not transduced T cells, such as tumor infiltrating T cells).

The “stem-ness” concept reminded me of older literature that aimed to dissect the basis for long-lived CD8+ T cell memory in the context of viral immunity (see here for a recent review: http://journal.frontiersin.org/article/10.3389/fimmu.2012.00357/abstract). There were at one time two broad classes of thought – first, that such memory required a consistent supply of antigen, for example, a depot that periodically re-stimulated the antigen-specific T cell population. The second school of thought, more reminiscent of the Busch finding, was that memory CD8+ T cells were self-renewing, and therefore did not require life-long antigen stimulus. The “big bang” hypothesis of T cell memory development, a hypothesis that the work of Dr. Busch and colleagues has definitively supported (see: http://www.bloodjournal.org/content/124/4/476?sso-checked=true) holds that once stem-like T cell memory is created, these cells can be used just like stem cells, i.e. to reconstitute cellular function, in this case, the ability to control viral infection.

Let’s get back to CAR T cells. Recent work has demonstrated clearly that the establishment of persistence in cellular therapy requires a robust response to abundant antigen. Only then can CD8+ T cell memory develop and from that point on be maintained. This observation informs the next set of studies, presented at the Clinical Application of CAR T Cells conference (#CART16 – https://www.mskcc.org/event/car-t-cell) held at the Memorial Sloan Kettering Cancer Center, the Adoptive T-Cell Therapy Congress held in London (http://tcellcongress.com/resource-center/) and the Advanced Cell Therapy Symposium (https://www.immunology.org/document.doc?id=1807) held at Guy’s and St Thomas’ NHS Foundation Trust and King’s College, also in London. Much of the work presented highlighted at these meetings addressed attempts to move CAR T cells into solid tumors.

Here I am a little hamstrung, as I’m relying on information presented on slides (as shared on Twitter by @JacobPlieth @VikramKhanna and others). Let’s try to define some themes here regardless.

Jacob has reviewed some #CART16 data: http://epvantage.com/Universal/View.aspx?type=Story&id=627150&isEPVantage=yes. Please see that link for his viewpoints.

First, to stick with CAR19 therapeutics, we have some posted Novartis data on responses in Non-Hodgkin Lymphoma (NHL). NHL is comprised of diverse B cell lymphomas, some of which are highly refractory to treatment. Examples of the refractory class include diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) among others. Here we see some rather impressive results treating these lymphomas:

The data are hard to read, but let’s pull out some numbers from the table. Note that essentially all patients got the optimal dose of 5 x 10e8 cells (1 exception) and that the peak cellularity is defined as %CD3+/CAR19+ cells in peripheral blood. We can therefore look at expansion, time to peak cellularity and outcome:

There seems no correlation between day to peak and outcome, unless it is very short – day 1 or 2 – and even then that is likely due to abortive expansion. If we arbitrarily set 10% as an exploratory setting with which to parse the %CD3+/CAR19+ data we quickly see that above 10% (black line), half of the patients responded, which below 10% only a third of patients responded. So expansion is important, as we already knew. With respect to the earlier discussion, we do not know the critical variable at work here, be it CAR T cell persistence (likely), CAR T cellular composition (per Riddell), patient variability, antigen density, or something else.

The FL data are a little bit more confusing:

Again we can pull out some of the data:

And now we are really hard-pressed to see any correlation between outcome and peak cellularity, no matter where we might draw the arbitrary line for analysis. What data is missing? I suspect it is a measure CAR T cell persistence over time, as this is most often associated with positive response. We should note that CD19 is an unusual target antigen in that it is expressed on the cancer cells (B cell leukemia or lymphoma) and on normal B cells that we can deplete without undue harm to the patient.

Other B cell antigen targets are under development as CARs, including CD22 and BCMA. BCMA is expressed on plasma cells (relatively uncommon B cells that secrete antibodies) and on essentially all multiple myeloma cells. Early promising results generated using a BCMA CAR to treat multiple myeloma were presented at ASH (http://www.ascopost.com/issues/march-10-2016/car-t-cell-therapy-may-have-role-in-treating-multiple-myeloma/).

Updated results are a little less encouraging as the complete response patient (#10) has since relapsed as was reported at #CART16. It is unclear if advanced multiple myeloma is simply more refractory to CAR treatment, if the lower cell number infused led to poor persistence, if the CAR were different, or if antigen load was too low. Thus we are again faced with multiple variables to assess.

So now we can ask what happens when there is little or no persistence, which is the case with most CARs directed to solid tumors. This is data from Nabil Ahmed and Stephen Gottschalk from Baylor College of Medicine. This group is collaborating with Celgene on cellular therapeutics. Here we see the results of treatment of HER2+ advanced solid tumors with CAR-HER2 T cells. The response is minimal.

This is very likely due to the very short persistence of the CAR-HER2 T cells, in most cases gone in a week or so.

Interestingly, analysis of resected or biopsied tumor after treatment revealed that the CAR T cells had migrated preferentially into the tumor, but had not proliferated extensively. Novartis presented nearly identical data on an EGFRvIII targeting CAR T cell study at the Boston PBSS Immuno-Oncology Workshop (http://www.pbss.org/aspx/homeBoston.aspx), and similar data has been presented on a host of solid tumor targets.

To return briefly to CD19+ tumors, it was reported recently that the response to CAR19 therapy in chronic lymphocytic leukemia was about 25%, but that all of those responders were durable complete responders (i.e. potential cures). Why the seemingly digital nature of response here? Again this is most likely due to CAR T cell persistence which itself is most likely a reflection of antigen load (among other variables). With this in mind I was struck by a slide from Seattles Childrens Hospital (I’m not sure from which meeting):

In point #3 the presenter is basically suggesting injecting an artificial antigen presenting cell expressing CD19, i.e. increasing the antigen load.

We can conclude by saying that there is a fundamental issue with CAR T cell antigens – those that are tumor specific are either not abundantly expressed and/or have been removed during the course of therapy. This is an issue that may not be solved by adding 4-1BB or IL-12 or anti-PD-1 antibody or whatever other immunological “help” one might envision. This issue impacts the entire field, which is why we now see analysts who once talked of the emergence of dominant CAR T platform companies now wondering who will win the CAR19 race to the finish line. That is still a noble race to run, but the patient numbers cannot justify the number of companies competing for the prize. Yet change will come and progress will be made…

What to do?

stay tuned.

ps. thanks again @JacobPlieth @VikramKhanna and others for kindly sharing slides (and getting great seats at conferences!)

Snow Day Reading: The New Multiple Myeloma Therapeutics

February 14, 2015$CELG, biologics, Celgene, daratumumab, Genmab, Johnson & Johnson, Lymphomas, Leukemias, Myelomas, monoclonal antibodies, myeloma, Onyx, SanofiPaul Rennert

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There was a comment floating around Twitter that “Biotech was boring this week” and that’s true, it has been a slow news week. Sanofi took the ax to about 100 Genzyme site staffers, Bayer and J&J announced R&D reorganizations, another CAR T cell deal got done (China) and IPOs and follow-on financings were announced: business as usual.

In the background though, slow but steady therapeutic advances are being made that will impact long-term company values. The development of antibody-based therapeutics in multiple myeloma (MM) is one nice example. Among the hematologic malignancies MM is a major disease. The incidence in the US is ~30K yearly and the prevalence is ~85K. A quick glance at that math reveals a disease with pretty short-term survival, less than 5 years according a report produced by the Leukemia & Lymphoma Society in 2014.

The age of onset for MM is 70 years old in the US, and this is important because it limits some treatment options for many patients who are physically frail. Such patients may not be candidates for high-dose chemotherapy and stem cell transplantation (SCT) and even patients who are given this first line regimen will eventually relapse. Those patients are served by second line therapeutics, described below.

The huge advance is this field has been the development of non-chemotherapeutic drugs. The IMiDs such as lenalidomide and pomalidomide (Revlimid^tm and Pomalyst^tm, both from Celgene), are used with the proteasome inhibitors such as bortezomib (Velcade^tm from Takeda) or carfilzomib (Kyprolis^tm, from Onyx) along with steroids (dexamethasone, prednisone) in various combinations. “Triplets” are the preferred therapeutic, as exemplified by the combination of lenalidomide, bortezomib and dexamethasone.

At the ASH conference in December a large retrospective outcomes study of newly diagnosed MM patients was presented (link 1). Here is some of the data from that study:

Cohort % Probability of 3 yr Survival

All ages (N = 1444)	63
< 65	70
65 to < 75	65
≥ 75	47
SCT
Yes	77
No	54
Triplet therapy
Yes	69
No	55
IMWG risk
High	59
Standard	66
Low	76
del(17p)
Present	53
Absent	63

So a few things here to note: age of onset is a negative factor for survival, in part due to the inability to get the majority of elderly patients to autologous stem cell transplantation (ASCT). In addition to age of diagnosis, the International Myeloma Working Group

(IMWG) risk score is a composite of factors that determine outcome, and finally the presence of a chromosome deletion (called del(17p)) is known to be associated with significantly shortened survival.

In this study they demonstrated further that the use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk but no improvement was noted for triplet vs. non-triplet therapy in patients with del(17p). Two things are clear from this study – one, we have patient subsets that remains underserved (the elderly and those patients carrying del(17p), and two, triplet therapy is keeping 70% of patients alive for at least three years.

What about patients that fail triplet therapy and who relapse and or are refractory to further treatment (rrMM)? They fare very poorly indeed, as shown here:

newly diagnosed treatment failures

There are a variety of novel therapeutics moving forward in rrMM, including novel proteosome inhibitors, HDAC inhibitors, nuclear export protein inhibitors and any others. One class of therapeutic gaining significant attention are the antibodies directed to the MM cells. These include the antibodies to CD38 and other MM-selective cell surface proteins.

The lead therapeutic among the anti-CD38 antibodies is daratumumab from Genmab in collaboration with Janssen. The deal included a US$55 million upfront payment, an $80 million equity stake in Genmab, and milestone payments adding up to $1.1 billion or more.Daratumumab is a huMAX CD38 mAb which kills CD38+ tumor cells via CDC and ADCC activity and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Additional activity may be due to apoptosis upon secondary cross-linking and modulation of CD38 enzymatic function (see ASH 2014 abstract # 3474). Daratumumab received the FDA’s breakthrough therapy designation in May 2013 for treatment of rrMM (for patients failing 2 lines of therapy).

When combined with lenalidomide and dexamethasone (len/dex), daratumumab produced an overall response rate (ORR) of 75% in the phase I dose ranging clinical trial. The trial was designed to accommodate an expansion cohort dosed at the MTD (maximum tolerated dose) of 16mg/kg. In the expansion cohort the ORR was ~ 92%.

In a phase Ib study daratumumab was combined with various regimens:

These efficacy numbers are startlingly good. What will be really impressive is the associated duraton of response (DOR) and overall survival (OS) data once the trial is mature. In early February preliminary results from another Phase II study were announced. The study, called MMY2002, is listed as NCT01985126 on clinical trials.gov (link 2). This two-part study enrolled 124 rrMS patients who had received at least three prior lines of therapy, including both a proteasome inhibitor and an IMiD, or were double refractory to therapy with a proteasome inhibitor plus an IMiD. The primary objectives of the study were to define the optimal dose and dosing schedule, to determine the efficacy of two treatment regimens of daratumumab as measured by ORR, and to further characterize the safety of daratumumab as a single agent. Two doses of daratumumab were compared in part 1, at 8 mg/kg and 16 mg/kg. The expansion cohort (part 2) received the higher dose based on interim safety analysis of the initial dose comparison.

The ORR was 29.2% in the 16 mg/kg dosing group with a DOR of 7.4 months. We can expect additional data to be presented at a medical conference this year, perhaps ASCO or ESMO, and ASH or EHA. These data will support the breakthrough therapy designation for daratumumab in rrMM and may lead to a 2015 approval in this patient population, i.e. based on the phase II results.

Additional daratumumab trials include 5 phase III trials in MM, including a series of studies in newly diagnosed MM, therefore, as front-line therapy, and a phase II trial ((LYM2001) in hematological malignancies. The study will evaluate daratumumab monotherapy in three different types of NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL). The study is expected to start enrolling patients in 2015.

Sanofi Oncology is developing SAR650984 (SAR), is a human IgG1 antibody that targets CD38. TCD11863 (NCT01749969) is a phase Ib trial evaluating the combination of SAR with len/dex in rrMM: patients averaged six prior therapies. These prior therapies included the second line therapeutics lenalidomide (94%), pomalidomide (29%), bortezomib (94%), and carfilzomib (48%). Eighty four percent of patients were relapsed and refractory to a least one second line therapeutic. In the dose ranging phase, the highest SAR dose of 10mg/kg was well tolerated.

After a median 9 month follow up, the ORR was 58%, with a clinical benefit rate of 65%, including a 6% stringent complete response rate. In patients receiving the 10 mg/kg dose, the ORR was 63%. The median progression free survival (PFS) was 6.2 months for all evaluated patients but was not yet reached in patients who received fewer than three prior therapeutic regimens before entering the study.

Looking just at the 84% of who were relapsed and refractory to least one second line therapeutic, the ORR was 50%.

An interesting study presented at ASH in December suggested that Immunogenetic factors contributing to NK cell function influenced clinical activity in pts treated with SAR/LEN/Dex. Specifically, the presence of a high-affinity KIR3DL1, HLA-B Bw4-80Ile genotype was associated with high ORR and prolonged PFS. This suggests that the NK cell competency of the patient influences the ability of NK cells to become activated in the presence of tumor cells coated with SAR antibodies. This fascinating study (ASH 2014, Abstract # 2126) should stimulate investigation of mechanisms of NK cell activation that could be used in combination with SAR, assuming the presence of len/dex does not complicate the picture. There are additional clinical studies of SAR, listed here: link 3. These include a phase I/II study in hematologic malignancies.

In addition to daratumumab and SAR650984, Celgene and MorphoSys are collaborating on the development of the CD38 antibody MOR03087 (aka MOR202). This antibody is currently being investigated as monotherapy and in combination with len/dexamethasone or bor/dex in a phase I/II rrMM study (NCT01421186). The Morphosys licensing deal with Celgene included a $92M upfront, $60M equity investment and downstream milestones. Takeda is developing the anti-CD38 antibodies Ab79 and Ab19, currently in preclinical studies (link 4). Xencor has a CD3/CD38 bispecific program. The small private biotech Molecular Templates has an anti-CD38 antibody-drug conjugate program. There are likely other programs out there.

Elotizumab (ELO) from Bristol Myers Squibb targets a different MM antigen, SLAMF7 (aka CS-1). A presentation at ASH (abstract #2119) reported early results from a phase Ib study of ELO in combination with len/dex.ELO selectively kills SLAMF7-positive MM cells through both direct activation and engagement of NK cells. A multicenter, open-label, Phase Ib trial (NCT01393964) enrolled patients with newly diagnosed or rrMM and varying renal function. Renal function is a dose limiting feature of rrMM treatment and disease progression. ELO (10 mg/kg) plus len/dex was given in 28-day cycles until disease progression or unacceptable toxicity. 26 pts were treated, 8 with Normal Renal Function (NRF), 9 with Renal Insufficiency (RI), and 9 with End Stage Renal Disease (ESRD). 89% had received prior therapy (median 2 regimens). Prior bor, thalidomide, or len treatment occurred in 21 (81%), 11 (42%), and 9 (35%) patients, respectively. ORRs were 75% (NRF), 67% (SRI), and 56% (ESRD). Thirty-eight percent NRF, 56% of SRI, and 11% of ESRD patients had a very good partial response or better. Therefore ELO/len/dex was well tolerated and showed clinical responses in MM patients regardless of renal function.

These new therapeutics for MM will certainly complement the existing triple therapies, giving patients added hope and time. We certainly expect that one of the new combinations of antibodies and the second line “triple therapeutics” discussed above will have an even more dramatic impact on MM when given in the front-line setting.

In the meantime Janssen (J&J) and Genmab are poised to give Celgene some real competition in the MM space.

The Reading List – Day 1

December 31, 2014genomics, Lymphomas, Leukemias, MyelomasPaul Rennert

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Last week I posted a holiday reading list (link). I’ll be posting brief summaries of some of the more interesting papers over the next week or two.

Topic: Tumor Mutational Landscape

The Papers

Age related variants of variants occurred in the genes DNMT3A, TET2, and ASXL1 are associated with hematological malignancy risk – NEJM-1 and NEJM-2
Nature Genetics on the NEJM papers: Commentary

The Highlights

– Interesting papers on the power of whole exome and targeted gene sequencing – and a large number of patients followed for a long time – to uncover putative initiating cancer mutations. These can be termed initiating in the sense that they predate the occurrence of malignancy.

– Both studies identified somatic mutations in peripheral blood mononuclear cells that occurred more frequently in patients who developed hematological malignancies than those who did not.

– Here is a peak at some of the data. This first figure is from the paper out of Benjamin Ebert’s lab at Brigham & Women’s Hospital, Harvard Med School, Boston.

On the left we see the 10 most commonly detected mutated genes, on the right the distribution of mutated genes per patient – overwhelmingly just one (Fig.2 from Jaiswal et al. 2014).

The second paper is from the McCarroll lab at the Broad Institute, MIT and Harvard, Cambridge, MA, across the river from Boston. Their list is a little different, as seen in this figure:

Notably, however, the top three genes are the same (Fig. 2 from Genovese et al. 2014).

Many of the other mutations are in genes well studies in the context of hematological malignancies (JAK2, IDH2, MYD88) and other tumors (TP53, STAT3). The differences are mainly in the rarer mutations and reflect statistical noise, the difference in patient populations studied, or both.

– The top 3 somatically mutated genes are various types of DNA transcriptional regulators. This suggests that the drivers for these malignancies are actually the targets of the activity of DNMTA3 (a DNA methyltransferase), TET2 (a methylcytosine dioxygenase) and ASXL1 (an epigenetic regulator). All three had been previously identified as mutated genes in patients with various lymphoid and myeloid malignancies, however these new studies show the mutations to be present and stable years before cancer develops.

– These somatic mutations are one-hit wonders, that is, they are clonal, and very likely causative. The McCarroll group’s paper has a nice figure illustrating this principal:

Thus clonal hematopoiesis evolves from one of the initiating mutations.

– A few other very interesting messages in these papers:

1) the number of mutations increases with age
2) mutations predict malignancy, but at a pretty low rate
3) mutations are associated with survival

The association with survival is not only due to the link with cancer: mutations in these transcriptional regulators appear cause other physiologies as well. The Ebert paper finds an association between age-related somatic mutations and cardiovascular disease for example. I’d caution here that this paper studies patients already predisposed to develop cardiovascular disease, and so this association might wash out in general population studies. Regardless, the relative risk of carrying one of these somatic mutations is not large, so it is not as if we should all run out and get these genes analyzed.

– Finally, and this has been known for a while, mutations in these transcriptional regulators are really problematic once cancer develops, and that is shown by the impact on overall survival post-diagnosis. This last point is very intriguing as it suggests that somatic mutations in transcription regulators do two distinct things, probably via action on distinct targets – one, predispose to hematologic oncogenesis and two, allow mutations to accumulate once oncogenesis has taken place.

Given that the relative risk of carrying any of these somatic mutations remains very low, what are we to do with the data? Genovese et al. anticipate this question, and offer the following (quoting here):

“Several important research directions could bring DNA sequencing for clonal hematopoiesis closer to clinical usefulness. First, some somatic mutations are likely to be associated with a particularly high risk of subsequent cancer; larger studies could identify such mutations. Second, single-cell analyses might identify high-risk combinations of mutations occurring in the same cells. Third, the sequencing of specific cell types might identify mutation–cell-type combinations with increased predictive value. Fourth, initial detection of clonal hematopoiesis might justify periodic screening for the presence of cooperating mutations at low allele frequencies that could presage cancer”.

I would add that a more detailed understanding of how somatic mutations in the DNMT3A, TET2, and ASXL1 genes trigger and support oncogenesis may yield downstream targets suitable for therapeutic intervention.

next topic: New Immunotherapy Papers

stay tuned.

Holiday Reading

December 24, 2014CRISPR, fibrosis, immunology, inflammation, autoimmunity, fibrosis, immunotherapy, IPF, lupus, Lymphomas, Leukemias, Myelomas, MS, oncology, TALEN, TILs, tumor microenvironment, Zinc Finger NucleasePaul Rennert

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some of the stuff we’re reviewing over the holiday break. N.b. paywalls ahead! And at the very end, some current non-science favorites.

Tumor Mutational Landscape

Age related variants of variants occurred in three genes (DNMT3A, TET2, and ASXL1) are associated with hematological malignancy risk http://www.nejm.org/doi/full/10.1056/NEJMoa1408617 and http://www.nejm.org/doi/full/10.1056/NEJMoa1409405

News and Views on the NEJM papers http://www.nature.com/nrg/journal/vaop/ncurrent/full/nrg3889.html

using siRNA to identify driver genes in breast cancer http://www.nature.com/nrg/journal/v16/n1/full/nrg3875.html

Immunotherapy

a primer on the role of PD-1 pathway inhibitors in Hodgkin’s Lymphoma, from Nat Rev Clin Oncol http://www.nature.com/nrclinonc/journal/vaop/ncurrent/full/nrclinonc.2014.227.html

the role of TILs and TIL-associated TNF in the survival of CRC patients http://www.jci.org/articles/view/74894

nivolumab in metastatic RCC, published data http://jco.ascopubs.org/content/early/2014/12/22/JCO.2014.59.0703.abstract

resistance to T cells in melanoma (hint: they lose MHC expression) http://clincancerres.aacrjournals.org/content/20/24/6593.abstract

interesting look at PD-L1 expression of the response of RCC to targeted therapies http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14-1993.abstract

it’s hard to control ipilimumab-induced tox http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14 2353.abstract

IO combination review http://clincancerres.aacrjournals.org/content/20/24/6258.abstract

tumor/microenvironment cross-talk mediated by microRNAs http://clincancerres.aacrjournals.org/content/20/24/6247.abstract

functional blockade of miR-23a releases TILs in an ex vivo NSCLC assay http://www.jci.org/articles/view/69094

neutrophils, T cells and lung cancer http://www.jci.org/articles/view/77053

Given the new immunotherapy data in bladder cancer, a review of the molecular drivers of this tumor type is most welcome http://www.nature.com/nrc/journal/v15/n1/abs/nrc3817.html

MDSC requirements for survival http://www.cell.com/immunity/abstract/S1074-7613(14)00436-1

Gene Therapy and CAR T

Novel gene therapy methods puts a safety brake on a retrovirus-based vector http://www.nature.com/nrd/journal/v13/n12/full/nrd4495.html

a new review of the CRISPR, Talen, and ZFN technologies for gene editing http://www.jci.org/articles/view/72992

NY-ESO-1 CAR T P1 results in solid tumors: long term follow-up and correlates of response http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14-2708.abstract

Targeted Therapies

A very timely primer of the role of different PI3K isoforms in diverse cancers http://www.nature.com/nrc/journal/v15/n1/abs/nrc3860.html

a Notch in the cancer treatment belt? Nope, a bit of a toxic mess made with anti-DLL4 antibody Demcizumab from OncoMed http://clincancerres.aacrjournals.org/content/20/24/6295.abstract

IL-17 and colon cancer? http://www.cell.com/immunity/abstract/S1074-7613(14)00446-4

Hematological Malignancies

von Adrian and Sharpe tease apart Follicular Lymphoma http://www.jci.org/articles/view/76861

the role of one of gp130 in multiple myeloma http://www.jci.org/articles/view/69094

Fibrosis, Inflammation, Metabolism, MS

a brand new fibrosis review http://www.jci.org/articles/view/74368

the TRPV4 pathway, TGFbeta and IPF http://www.jci.org/articles/view/75331

The role of novel branched fatty acid esters of hydroxy fatty acids in Type 2 diabetes http://www.nature.com/nrd/journal/v13/n12/full/nrd4501.html

will STING finally yield a useful target in lupus? http://www.jci.org/articles/view/79100

an animal model of JCV infection and PML http://www.jci.org/articles/view/79186

Investment and Deals

Pharma funding to pull programs out of the academic space http://www.nature.com/nrd/journal/vaop/ncurrent/full/nrd3078-c2.html

some color from NRDD on the Genentech + NewLink IDO-1 inhibitor deal http://www.nature.com/nrd/journal/v13/n12/full/nrd4502.html

Also notable

300,000,000. A violent graphic lurid hypnotic novel of the dissolution of consciousness and the consequence of multiple realities converging within our unprepared empty minds and upon our decadent culture. Horrific and wonderful, but not for the squeamish.

Thug Kitchen – eat like you give a #$%@^. Fun, but you get the idea.

Death & Co: Modern Classic Cocktails. Drink like an adult.

The French Connection – Lirilumab Edition

November 2, 2014AML, Bristol Myers Squibb, immunotherapy, Innate Pharma, lirilumab, Lymphomas, Leukemias, Myelomas, monoclonal antibodies, oncology, PD-1Paul Rennert

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Bristol-Myers Squibb (BMS) has quietly changed the protocol of clinical trial NCT01592370. This Phase 1 clinical trial has evolved from a nivolumab (anti-PD-1) study in hematological malignancies (5/4/14) to include ipilimumab (anti-CTLA4) with nivolumab (4/8/14) to now include nivolumab, ipilimumab and lirilumab (anti-KIR) as of 10/30/14. The changes were noted on Twitter (where else?) by several biotech experts who posted this screen shot:

The striking thing to notice is the addition of lirilumab across the board.

The clinical trial includes the following indications/inclusion criteria:

Subjects must have histological confirmation of relapsed or refractory hematologic malignancy
Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma must have at least one measureable lesion >1.5 cm as defined by lymphoma response criteria. Tumor sites that are considered measureable must not have received prior radiation therapy
Subjects with Multiple Myeloma (MM) must have detectable disease as measured by presence of monoclonal immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM,(M-protein ≥0.5 g/dl or serum IgD M-protein ≥0.05 g/dl) or serum free-light chain or 24 hour urine with free light chain. Excluded are subjects with only plasmacytomas, plasma cell leukemia, or non-secretory myeloma
Subjects with Chronic myelogenous leukemia (CML) must have evidence of the Philadelphia chromosome by polymerase chain reaction (PCR) or chromosome analysis
Life expectancy of at least 3 months
For subjects with lymphoma, either an archived Formalin fixed tissue block, or 7 to 15 slides of tumor sample for performance of correlative studies
Subjects must have received at least one prior chemotherapy regimen. Subjects must be off therapy for at least 3 weeks (2 weeks for oral agents) prior to Day 1

The trial covers Non-Hodgkin Lymphomas (NHL), Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Acute Myelogenous Leukemia (AML), a subset of Chronic Myelogenous Leukemia (CML) and other hematologic malignancies. The requirement for biopsy tissue is to support biomarker analyses.

Lirilumab is an antibody developed by Innate Pharma (IPH.PA) that binds to the KIR2DL1, -2, and -3 receptors and prevents them from binding to HLA-C. HLA-C is a B2-microglobulin bound MHC family member with antigen presenting function. As an ancient system of antigen presentation, HLA-C is expressed on virtually all cell types. Binding of HLA-C to KIR2DL isoforms induces an inhibitory signal that prevents NK cells from engaging in cytotoxic control of tumors. By preventing KIR-mediated suppression of NK cells, lirilumab increases NK cell–mediated killing of HLA- C+ tumor cells.

Lirilumab showed signs of clinical activity in a Phase 1 trial and acceptable toxicity was observed (Vey et al. 2012. Blood 120: 4317, Vey et al. 2013. Blood. 122: 21, abstracts). A Phase II study of lirilumab in AML is in progress and combination Phase 1 trials of lirilumab in combination with ipilimumab and nivolumab for a variety of tumor types have begun. Lirilumab is also being tested in combination with the depleting antibody elotuzumab (anti-CS1) in refractory MM. The lirilumab-titled trials are listed below:

So what to make of all this activity? One reasonable conclusion is that enough data from interim analyses of the AML trials has come in to convince BMS to double-down on the partnership with IPH and move lirilumab forward aggressively. The breadth of indications is impressive. A second, related, conclusion is that preliminary data on lirilumab’s clinical activity in AML is ready for presentation at the American Society of Hematologists (ASH) Conference in December. The abstracts from that conference will come out on November 6th, so we’ll see.

There is considerable interest in combining T cell directed immune checkpoint therapeutics with those that act on NK cells. Innate Pharma (IPH.PA) has additional programs of interest in the NK cell space, including an antibody that targets MICA, a negative regulator of NKG2D-mediated activation of NK cells and an antibody that targets NKG2A, an inhibitory receptor.

The focus of this company on NK cell biology is impressive and may finally drive strong valuation. Innate has some very vocal supporters, but many investors seem reluctant to back this company. One reason perhaps is that it trades in Europe and liquidity of the corresponding US shares (OTC:IPHYF) is low. Another reason is perhaps the relationship with Novo Nordisk, which owns about 15% of company equity. From the scientific perspective the company is innovative and exciting, and I would love to have someone explain the stock valuation issues. Innate raised significant capital earlier this year with a round led by Orbimed, Redmile, FMR and about a dozen other top tier investors. An early look at AML results for ASH, or perhaps at ASCO, and strong clinical data thereafter could make many retail and institutional investors happy.

stay tuned

Yelling Yellen and The Least Licensable Unit (LLU)

July 16, 2014ADC, biologics, chimeric antigen receptors, immunotherapy, monoclonal antibodies, oncology, PD-1Paul Rennert

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In grad school we laughed about the LPU (Least Publishable Unit), those 2 or 3 crappy papers that should have been one better paper.

Today lets introduce the Least Licensable Unit, the LLU. Amidst all the angst and anger directed at the Fed chair yesterday it occurred to me that excessive valuation has a trickle-down effect. When anything is worth too much, almost nothing is still worth a little. That almost-nothing is an LLU. When we look at the current state of asset acquisition in the immuno-oncology (IO) space we see this clearly. Very early stage assets are being land-grabbed by very large companies, and a certain sly sense of glee has crept up the brainstems of savvy biotech entrepreneurs who are rightly looking at looking at IO assets as the rarest of gemstones. Even the mere hint of sparkle in an otherwise dirt sample has prospectors racing to the wilds of Waltham and the coffee shops of Cambridge looking for LLUs.

Why is this? A few years ago (a very few) you would need to drag a program right up to the threshold of IND enablement in order to attract any attention at all. Your IP would have to be rock solid and be good for 30 years (with extensions, I know I know). Preclinical pharmacology? check. Repeat dose toxicology? check. Non-human primates? of course. A validated biomarker program? well underway!

What changed? Pretty simply, IO creates a paradigm shift in the way oncology (and many other diseases) are treated. Think rheumatoid arthritis, psoriasis and Crohn’s disease before anti-TNFs. Multiple sclerosis before beta-interferons. HCV before Vertex, Gilead and Abbvie. We are looking at a similar level of evolution in clinical practice across the whole of oncology – meaning massive disruption. With the stakes this high you have to get out, or go big. And so we see that big bets and lots of them are the order of the day. But now, a few years in, the hunt for quality is harder, and programs are taken early. The hunt for assets is so intense that the academic licensing groups at our top tier universities and medical centers are overwhelmed with inquiries. The beautiful thing here is that such leaps of faith (lets face it) are now less risky in part because technologies are rapidly differentiating. Are you in danger of stumbling into patents that block your CAR T designs? Bolt on a gene editing company and tinker so you can move into new ip. No room for your new PD-1 antibody? Blaze trail to a newly defined epitope and defend your little patch. With so many companies applying technology to assets, novel composition is easier to define. You might be able to fix an LLU, make it better, make it into a drug.

All such asset stampedes eventually run into a wall of diminishing returns as the front runners take off and the leftovers get trampled by too many competitors. That is starting to happen now in IO. Yes, it is. So what do we do now? I have a few ideas:

1) Sifting through LLUs take hard-core due diligence, so let us know if we can help

2) It is going to be harder to partner “me too” assets – programs need to differentiate or better yet track novel biology

3) In IO the T cell space is not played out yet, but we should be looking at NK cells and myeloid lineages for extra traction, and watch for the development of novel immune checkpoint pathways and better agonist antibodies (or both)

4) The CAR T space seems overwrought – I think this has to settle out over a few years – but despite this I also expect to see a big wave of new companies emerge from stealth in the next 0 – 18 months

5) Bispecific antibodies and ADCs will quietly advance to capture a dominant position in IO

6) Finally if you are looking for or have a beautiful asset, seek help in partnering – you’ll save time and wind up in a better partnership (sure, call me, this is what we do best)

cheers all, and stay tuned

ADC snapshots from #ASCO14

May 27, 2014#ASCO14, ADC, ALL, biologics, immunotherapy, Lymphomas, Leukemias, Myelomas, monoclonal antibodiesPaul Rennert

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We present a table outlining top tier results for antibody-drug conjugates (ADC). The tables will be updated as we come across additional abstracts and new data

Silo Busting: Can We Build Better Immunotherapies for the Treatment of Prostate Cancer?

April 30, 2014CAR-T, chimeric antigen receptors, immunotherapy, Lymphomas, Leukemias, Myelomas, oncology, Prostate CancerPaul Rennert

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A very interesting paper published last week in Cancer Research. Written by investigators at The Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, the paper addresses unmet need in prostate cancer (PC), and proposes a multi-modality approach to building an effective therapeutic. The authors are Nathaniel Brennen, Charles Drake and John Isaacs and title is Enhancement of the T-cell Armamentarium as a Cell-based Therapy for Prostate Cancer. The abstract is here.

The authors review the state of hormone-treatment and chemotherapy refractory, metastatic, and/or relapsed prostate cancer, collectively mCRPC. Approximately 200,000 patients (male) are diagnosed with PC each year in the US. Deaths from mCRPC number roughly 30,000 men/year in the US, and there are very limited treatment options. Potential therapies include PC vaccines like Provenge and others in clinical development (GVAX, ProstVax). Notable for anticipating the need for broad immune stimulation ProstVax uses viral vectors which encode prostate-specific antigen (PSA) along with costimulatory molecules B7.1, ICAM-1, and LFA-3. More conventionally, Provenge and GVAX are composed of prostate cancer cells that are irradiated and then engineered to express the immune molecule GM-CSF. Provenge uses patient-derived tumor cells while GVAX uses PC tumor cell lines. Provenge offers a modest survival advantage versus the standard of care chemotherapeutic, docetaxel. GVAX failed to meet its primary end point of overall survival when compared with docetaxel in a phase III study. In a phase 2 study, ProstVax treatment led to a median overall survival (OS) of 25 months, very similar to Provenge (vs. 17-22 months in the placebo groups, respectively). Many other variations on this methodology are in development. Other immunotherapeutic approaches in the pipeline include antibodies such as Vervoy (ipilimumab) and nivolumumab that have shown efficacy in other solid tumors. The anti-CTLA4 antibody ipilimumab, a potent immune checkpoint modulator, is being evaluated in mCRPC, both alone and in combination with chemotherapy, radiotherapy or tumor vaccines. Current phase 3 trials include ipilimumab vs placebo in chemotherapy-naïve patients and a second trial in patients who have first received chemotherapy and bone irradiation. Early results suggest that previously treated patients obtain minimal benefit from ipilimumab but that newly diagnosed patients perhaps fare better. Surprisingly, early clinical studies with the anti-PD-1 antibody nivolumab failed to show any benefit. Another approach will be to build T cell therapies such as those based on chimeric antigen receptors (CARs) that have been successful in treating leukemia and lymphomas. However, while known mCRPC antigens are certainly overexpressed in tumor cells, they are not uniquely expressed. For example folate hydrolase (PSMA), a targeted mCRPC antigen, is also expressed, albeit at low levels, in the kidney, small intestine and both the central and peripheral nervous systems. The prostate stem cell antigen (PSCA), another mCRPC antigen, is also expressed in the bladder, colon, kidney, and stomach. Given the inherent aggressiveness of CAR T cells, targeting these antigens is dangerous business indeed.

Back to the paper. Instead of just stating that we need to mix novel immunotherapeutics until we find the right combination, the authors spend some time deconstructing this particular tumor type, and then rationally build up a therapeutic hypothesis based on what the tumor has shown them. This is of course the essence of the personalized medicine approach, although perhaps based more on critical thinking about the biology rather than cataloging driver mutations (both being needed in the bigger picture). And while their ultimate proposals may be overly engineered, they are certainly on an interesting track.

So what do PC tumors tell us? First, PC is often an indolent and slow growing tumor that is caught early by routine screening for soluble prostate specific antigen (PSA, we’ll come back to all these antigens later). Second, more than 80% of PC tumor biopsies have extensive inflammatory infiltration, showing that the immune system has recognized that something is wrong, but can’t seem to fix it. Third, the majority of cells within the inflammatory infiltrate are T cells, so we have the right cell population sitting there ready to kick off a defense (but they don’t).

This is a situation that resembles that of melanoma, that is, a solid tumor that is filled with disabled immune cells, many of them T cells. The difference is that melanoma can be effectively treated with ipilimumab, nivolumab and, very strikingly, with the combination of the two. We reviewed the synergy of immunotherapy treatments for melanoma in our prior post.

So why are PC tumors different? The T cells appear either “exhausted” and unresponsive (anergic T cells), or are actively immuno-suppressive T-regulatory T cells (Tregs). They are identified by expression of specific transcriptional factors (FoxP3) and cell surface proteins (CTLA4, PD-1, and others). They respond preferentially to specific factors that keep them quiescent or immuno-suppressive (IDO, TGFbeta, IL-10). Basically they are so loaded down with redundant and compensatory off-signals that they simply will not be roused by any single method – not a vaccine, not an immune-checkpoint antibody, not even, it seems, when given in combination. A bigger stimulus is needed.

And this is where Brennan et al. lead us in their recent paper. They begin by introducing a CAR built by the team at Memorial Sloan Kettering Cancer Center in New York, led by Michel Sadelain. As a reminder, most CAR constructs contain a single domain for antigen recognition, usually derived from an antibody. We discussed the technology earlier (see this post, and related posts from March). So, for example, the CAR constructs used to transduce T cells that successfully treat acute and chronic leukemias (ALL and CLL) all recognize the antigen CD19. The CAR proposed by the MSKCC group has two antigen recognition sites, one for PSMA and one for PSCA. As noted above, neither of these antigens alone is specific for mCRPC, nor would I imagine the combination to be 100% specific. As someone tweeted during AACR: “A PSMA CAR? Their gonna kill someone with that drug”. Suffice to say, that’s one problem with the dual-targeted CAR. Another, more theoretical, is presented by Brennen et al. as a problem of effectiveness. This is a curious argument. The author’s state that all CAR therapies “share a dependence on endogenous T-cell effector functions”. This is maybe an unfortunate choice of “endogenous” since the activity of CAR-T cells is certainly not endogenous but rather artificially driven by the construct with which it is transduced. The available data suggest that such activity is considerable and dependent only on the availability of antigen. Whether CARs will shut down once they encounter the immunosuppressive environment of the mCRPC tumor is a different question that has nothing really to do with endogenous effector function. But lets move on and take their point for the sake of discussion as it drives the next interaction of their proposed therapeutic, which is to introduce a non-natural cytotoxic element to the CAR.

I suspect the authors are being provocative to make a point, but this seems a bit overdone. Still, lets soldier on. The proposal is now to create a Trojan Horse out of a CAR T cell, by arming it with a proform of a toxin. The example offered in proaerolysin, a vicious bacterial protein capable of blowing holes in every cell it encounters. The toxin is known from studies in which it was injected directly into tumors, in which setting it destroys every cell in a very small area, thus ineffectively. A second iteration of this strategy was to mutagenize the toxin by introducing a PSA-dependent cleavage site, thereby only releasing the active toxin in the presence of PSA, the PC selective biomarker used in routine testing. This Trojan Horse or “molecular grenade” creates a “kill zone” when cleaved by PSA.

To recap. We now have a dual CAR targeting PSMA and PSCA, carrying proaerolysin, that is activated by PSA. It actually get more complex then that, but lets just stop there, take a step back from this Rube Goldberg approach, and ask if we can find merit in the exercise.

There are two interesting concepts here, useful in their own right. One is to “mask” the CAR, irrespective of Molecular Trojan Kill Zones. One genuinely scary and unpredictable aspect of CAR technology is off-target toxicity. This has been seen repeatedly, and casts a long shodow over every new CAR antigen in development. Why? Because there is the “what if” aspect. What if the antigen is expressed somewhere else, unexpectedly, or what if the domain used for antigen recognition also sees a different, related, antigen on normal tissue? Both of these things have happened, and when these things happen, patients die, very quickly.

So, masking a CAR, even a single domain CAR is a very good idea. Happily this is a well worked field, with companies like CytomX busy working out the utility of using tumor-specific proteases to cleave specific peptide sequences that otherwise effectively mask antibody-drug complexes (ADCs) in an effort to improve their safety. That technology may be transferable in some form to CAR technology, providing an added layer of specificity without having to add up all these different tumor-selective antigens (PSMA, PSCA, PSA).

The second is to “arm” the CAR, masked or otherwise, with a toxin. This takes some thought but is possibly an attractive idea, if one could work out the geography (where to place the thing so it works where one wants it to work). I’m a little puzzled about the idea that you could add a toxin, in proform or otherwise, and avoid killing the transduced T cell. For example, PSA, used in the thought experiment above, exists in systemic circulation, a bad place to blow up your Trojan Horse.

Regardless the take-home message is that we might productively combine technologies across the immunotherapeutic space, to build better individual therapeutics.

Returning to mCRPC, where does immunotherapy actually stand, today. It’s fair although sad to say that progress here is similar to most other solid tumors, that is, there has been limited success. There is a vast amount of work to be done but happily there is an army of researchers and physicians willing to do it. With any luck at all papers like the one discussed in this post will help point the way, as loopy as a Molecular Trojan Kill Zone might sound today.

We’ll talk about iCARs next perhaps. or maybe BiKES. We’ll see.

stay tuned.

Three high-altitude take aways from AACR14

April 14, 201419-28z CAR, AACR14, ALL, B cell lymphoma, B cell lymphomas, biologics, BITE bi-specific, chimeric antigen receptors, CLL, CTL019, Ibrutinib, immunotherapy, Juno, leukemia, Lymphomas, Leukemias, Myelomas, melanoma, Merck, monoclonal antibodies, Novartis, oncology, Pfizer, rituximabPaul Rennert

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The American Association for Cancer Research (AACR) 2014 meeting last week was high energy and high impact. We will dive into particular talks and specific pathways and indications in later posts, in the meantime I wanted to mention a few key themes.

1) Immunotherapy Versus The World. That’s a deliberate overstatement of a subtle shift in emphasis from last year’s big meetings, where combinations of immunotherapy with just about anything else were the hot topic. This year there were several talks which emphasized the futility of chasing oncogenic pathways and all of their resistance mutations, one after the other, as opposed to letting the immune system do the work. However, it seems to me overly optimistic to believe that immune modulation can defeat a high percentage of patient tumors on its own, as some speakers acknowledged. Combinations remain necessary although we will have to work past some notable failures in combo trials, such as the liver toxicity seen in the ipilimumab + vemurafenib combination phase 1, discussed briefly by Antonio Ribas (see http://www.nejm.org/doi/full/10.1056/NEJMc1302338).

2) Immunotherapy Versus Itself. In the ultimate battle of the titans, we see different immunotherapeutic modalities squaring off. This is a theme we’ve touched on before in this space, but the competition is getting heated. In some indications, the leukemias, lymphomas, perhaps melanoma and some other solid tumors, there is an abundance of therapeutic choices, and the hard question of which therapy best suits which patient will ultimately need to be addressed outside of the context of clinical trial enrollment. Several talks really brought this message home. Roger Perlmutter of Merck (and before that, Amgen) envisions an important role for multiple immune therapies including bi-specific antibodies, chimeric antigen receptors (CARs), and immune checkpoint modulators like Merck’s anti-PD-1 antibody MK-3475. For B cell lymphoma for example, there is blintumumab (Amgen), a potent bi-specific that redirects T cells to CD19+ tumor cells (and normal B cells), and there is CTL019, a CAR therapeutic which does much the same thing. The therapeutic profiles and toxicity differ, but the general idea is the same. One big difference is that while CTL019 drives T cell expansion and the development of long term anti-tumor memory, the bi-specific does not. Which is better? We don’t know yet. He did not mention that one might do well trying a course of BTK inhibition plus anti-CD20 antibody therapy, perhaps with restricted chemotherapy first e.g ibrutinib plus rituximab and chemo (R-BR or R-F). That choice comes down to efficacy, then toxicity, and eventually cost. Efficacy seems to be a home run with the CAR therapeutics, although these may run into trouble in the area of toxicity and cost calculation. Renier Brentjens discussed the CAR therapies being developed under the Juno Therapeutics umbrella. Acute lymphoid leukemia (ALL) can be treated with CAR 19-28z modified T cells to achieve a >80% complete response rate with >70% of patients showing no minimal residual disease, an outstanding result. However, 30% of treated patients end up in the ICU due to cytokine release syndrome and other toxicity, and recently patients in the ALL trials have died from unanticipated tox causes. Juno stopped 5 trials of their CAR technology last week due to toxicity. Apparently one patient died of cardiovascular complications and another of CNS complications (severe uncontrolled seizures) – it was hard to nail down as Dr Brentjens had gone off his prepared talk for these remarks which were off the cuff, so comment please if you have better info on this. Carl June discussed Dr Brentjens’ presentation, noting that the clinical results were really quite striking, and contrasting the CD28 motif-based CARs with the 4-1BB-based CARs (as designed by Dr June with U Penn and licensed to Novartis). He also stressed that in chronic lymphocytic leukemia (CLL) they have had patients who have failed up to 10 prior therapies, including rituximab and/or ibrutinib, and these patients have responded to CAR treatment. That’s very impressive data. The roadblocks to widespread use of CAR therapy however are large and include the toxicity, the “boutique” nature of the current protocols, the cost. Perhaps, Dr June suggested, CAR will end up as third line therapy, reserved for salvage therapy. I for one hope not.

Also in the immunotherapy space were hot new targets (e.g. CD47, OX40, GITR), advances on the vaccine front, and a few surprises. We’ll update soon.

3) The Medicinal Chemists Have Been Busy. Not to be drowned out by the Immunotherapy tidal wave, small molecule therapies targeting specific oncogenic pathways continue to be developed and show promise. Most readers will be aware of the high stakes showdown (so billed) between Novartis, Pfizer and Lilly in the field of specific CDK4/6 inhibitors – in addition to bringing forward some really nice phase 2 data (we’ll discuss these another time) this “showdown” also illustrates that current portfolio strategy drives a lot of overlapping effort by different companies. As expected, much of the action is moving downstream in the signaling pathways, so we saw some data on MEK1 inhibitors and ERK1/2 inhibition. There were some new BTK inhibitors, nice advances in the epigenetics space, and some novel PI3K inhibitors. All grist for the mill.

stay tuned.