Category Archives: chimeric antigen receptors

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

Aleta 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, myelofibrosis, , , , ,

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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 40th 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 3rd or later to 2nd 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.

Yelling Yellen and The Least Licensable Unit (LLU)

ADC, biologics, chimeric antigen receptors, immunotherapy, monoclonal antibodies, oncology, PD-1

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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

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

CAR-T, chimeric antigen receptors, immunotherapy, Lymphomas, Leukemias, Myelomas, oncology, Prostate Cancer

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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

19-28z 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, rituximab

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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.

Update from AACR14: Clinical Halt for Memorial Sloan Kettering/Juno Therapy in Non-Hodgkin Lymphoma

19-28z CAR, AACR14, chimeric antigen receptors

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Yesterday we learned that the Memorial Sloan Kettering Cancer Center (MSKCC) and corporate partner Juno had stopped enrolling patients into 5 clinical trials of their chimeric antigen receptor (CAR) T cell therapies. Details are spare at this point, but unexpectedly, the cause of the clinical stop was severe cytokine release syndrome (CRS). I say ‘unexpectedly’ because it was just last month that MSKCC released an update on their ability to detect CRS early enough to initiate aggressive treatment. We commented on this update in a recent post on the CAR 19-28z technology.

According to the MSKCC update given in February, they had developed “guidelines for managing the side effects of cell therapy” including CRS, and “diagnostic criteria” for identifying at-risk patients using clinical lab tests. These tests were for a panel of cytokines and for C-reactive protein (CRP). To be fair these comments were made in reference to work ongoing in acute lymphocytic leukemia (ALL), but it was clear that the clinicians felt they were broadly applicable. It seems now that these comments were premature.

This is a critical issue in the CAR technology field, potentially holding back not just MSKCC/Juno but similar work from U Penn/Novartis and NCI and partners working with Kite Pharma. The syndrome characterized as CRS is a consequence of the massive immune response to the tumor, which is a designed consequence of the CAR technology. CAR-modified T cells are potent cytotoxic agents, and are designed to recruit unmodified T cells to the cause (the so-called bystander effect). This result is the triggering of the acute phase response, and then an outpouring of cytotoxic compounds, pro-inflammatory cytokines, and effector proteins. When allowed to proceed unchecked, the response begins to engulf normal cells and tissues, causing additional cell death, organ damage, and in the most severe cases, death.

The reality is that clinical responses leading to CRS seem to have caught MSKCC/Juno flat footed in at least one clinical trial of Non-Hodgkin’s Lymphoma (NHL) – we note here that stopping 5 trials does not mean that CRS was seen in all 5, but they are related by clinical indication, so it is an obvious precautionary step to take.

What will happen next we cannot know yet, as we have not yet heard the necessary detail. At the very least the MSKCC/Juno NHL programs are in for careful scrutiny. This will impact the clinical development of the technology and slow access for patients. The patients affected are those who are the most in need, nonetheless, the caution is warranted. More broadly, this unexpected turn of events may encourage us to look again at more established therapeutics for NHL, including small targeted molecule drugs, cytotoxic antibodies, antibody-drug conjugates (ADCs) and bispecifics, and of course, combinations of those therapies with one another or with current chemotherapeutics.

And this just in: In the immune checkpoint space we have just learned this morning of the potential for unexpected immune toxicity after long term treatment. Thankfully this appears to be very rare but this too will bear watching.

Kites Fly: Effective CAR-T Therapy in Non-Hodgkin Lymphoma? Hematological Malignancies Part 4

ALL, AML, B cell lymphoma, B cell lymphomas, CAR-T, chimeric antigen receptors, immunotherapy, Kite Pharma, lymphoblastic leukemia, Lymphomas, Leukemias, Myelomas, monoclonal antibodies

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Sorry for the slight delay getting this out. I was trying to account for each patient as even 1 or 2 misplaced will impact the response numbers in these small trials. Took a while.

Our last post focused on the CAR technology coming out of the MSKCC and affiliated institutions, being brought together under the Juno company umbrella. Juno was funded by ARCH Venture Partners and the Alaska Permanent Fund, through a partnership managed by Crestline Investors, along with Bezos Expeditions, and Venrock. We noted in closing that CAR T cell technologies were performing very well in acute lymphocytic leukemia (ALL), but not as well in the Non-Hodgkin Lymphomas (NHL). In early data sets response rates were not trending very high.

Recently I came across Kite Pharma’s JPM update on their version of CAR therapy. Kite is financed by Pontifax Ltd., Alta Partners, Commercial Street Capital, and individual investors, in partnership with the National Cancer Institute (NCI) Surgery Branch under a Cooperative Research and Development Agreement (CRADA). This reflects that the technology is coming out of NCI labs.

I was struck again by the duration and response rates reported and the indications they were pursuing. It seems that there is one extra patient in the JPM slide deck, so I went back to the ASH talk to get the right numbers. So lets review. Kite calls its lead CAR construct a very straightforward name: anti-CD19 CAR. Like 19-28z CAR from Juno/MSKCC, this CAR is built with a anti-CD19 scFv, followed by CD28 and CD3 signaling components. Quite unlike the 19-28z effort however, the lead here is NHL indications, specifically as seen here:

Screen Shot 2014-03-26 at 5.28.38 PM

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Hematological Malignancy Treatment Landscape. Part 3: My other CAR is a …

19-28z CAR, ALL, CAR-T, chimeric antigen receptors, CTL019, immunotherapy, Juno, lymphoblastic leukemia, Lymphomas, Leukemias, Myelomas

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A few folks kindly emailed to point out that I had not mentioned the Memorial Sloan Kettering Cancer Center (MSKCC) in my previous post. The sin of omission. Apologies, but I’ve been trying to digest the press release that the MSKCC put out on February 19th. The presser served two purposes I think, one valid (here’s some data) and one just pure PR grandstanding. Plus, the release didn’t link to the actual study. That was published in Science Translational Medicine the same day as I found out after some text searching, only to run into a paywall.

So, here is the referenced paper:

Davila ML et al. 2014 Efficacy and Toxicity Management of 1928z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. Sci Transl Med. Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.

The data from MSKCC investigators (the PIs are Renier Brentjens, Isabelle Rivière, and Michel Sadelain) is very impressive. In a small phase 1 study of patients with relapsed of refractory Acute Lymphoblastic Leukemia (r/r ALL), patient T cells were transduced with the CAR construct 19-28z CAR and reinjected into the patient. As seen with CTL019 (previous post), this is an effective strategy for producing a lasting T cell response to the CD19-positive leukemia. In the 16 patient trial, 88% of patients responded and just under half went on the receive allogenic HSCT, the standard of care for ALL. So thats great. Just to add some details, a complete response (CR) was reported for 14/16 patients. Two of these patients were already minimal residual disease (MRD)-negative when enrolled. The MSKCC study defines MRD- patients as CRm. The CRm is given as 75% so I’m guessing here that the 2 patients already MRD- at enrollment were not re-counted. Of these 75%, one third were further defined as CRi (CR with incomplete cellular recovery) meaning that they were cytopenic for one or more cell types. Other than this reference to toxicity, the paper generally focuses on cytokine release syndrome (CRS), noting that CRS can be accurately tracked using the routine clinical laboratory marker CRP. More importantly the investigators use a cytokine panel and CRP to define a severe CRS (sCRS) group of patients and a non-severe (nCRS) group of patients. Please note here that if you take the time to burrow through the supplemental tables you will find that both sCRS and nCRS patients had grade 3 and 4 adverse events including hypotension, febrile neutropenia, hyponatremia and altered mental state (CNS toxicity). sCRS patients (7/16 = 44%) further presented with fatigue, atrial fibrillation, sinus tachycardia, electrolyte imbalance, hypoxia and respiratory failure. It’s an important distinction, as the sCRS patients remained hospitalized, including ICU care, for an average of 57 days, versus 15 days for the nCRS group. Both groups are incurring very high health care costs post-treatment.

19-28z CAR differs from CTL019 in several interesting ways. The extracellular domain is a CD19-specific scFv. This is genetically linked to transmembrane and cytoplasmic domains from the costimulatory protein CD28, linked in turn to the CD3 epsilon signaling motif. CTL019 is similar overall, but uses 4-1BB domains instead of CD28 domains. One important consequence of the use of CD28 versus 4-1BB as the costimulatory effector domain is the persistence of the expanded T cell population after injection into the patient. For the 19-28z CAR T cells described in the present paper, the average duration was 3 months. The authors suggest that this is shorter than the duration seen with CTL019 treatment, and that this may be beneficial. That remains to be seen, as we really need duration of disease remission data to understand the benefit/risk of maintaining the T cells that control the leukemia. A final note on this: the MSKCC investigators go to some lengths to sketch out a clinical development plan that can be applied to various centers (not just theirs). This is a very important and useful development, which we would hope make these cellular therapies more widely available.

On the basis of this early data presented here and the phase 2 data coming from the U Penn group (see the prior post), its safe to say that we are watching the development of a new standard of care for ALL patients.

Back to the presser for a moment. The rest of the press release was amusing in a ballsy kind of way. There was the breathless prose and the very pointed “we were the first” claims that science journal editors (but not PR directors) generally avoid. As we all know, none of this science developed in a vacuum and the claim of precedence will be sorted out by patent courts as necessary. For the record I really have nothing against their PR campaign, it just makes me squirm a little. I happily support the MSKCC every year by donating through their Cycle for Survival Program (thanks to the strong legs of longtime friends John and Susan Canavari). Also I really look forward to watching this technology develop, along with technology from the Fred Hutchinson Cancer Center and the Seattle Children’s Research Institute, under the umbrella of Juno Therapeutics, which was formed in Seattle in December specifically to advance this and related therapies.

It’s pretty clear that this technology is very important and very very exciting.

Now, why don’t these cell based therapies work as well in other indications, like Non-Hodgkin lymphomas?

stay tuned.

Hematological Malignancies – who will win the battle for patients? Part 2: BiTEs & CARTs targeting CD19

ALL, Amgen, B cell lymphoma, B cell lymphomas, biologics, BITE bi-specific, CAR-T, chimeric antigen receptors, CLL, DART bi-specific, genetic engineering, immunotherapy, lymphoblastic leukemia, monoclonal antibodies, Novartis, oncology, rituximab

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 We talked last time about the potential of Macrogenic’s DART bi-specific technology and we focused primarily on the T cell engaging bi-specifics, such as DART006, a CD3 x CD123 therapeutic. Lets just quickly state the hypothesis:

Bi-specific modalities will allow the targeting of the patients T-cell driven immune       system to a precise (tumor-expressed) antigen.

Other outcomes are possible. For example, the drugs might not work at all, or they might not be as specific as designed, or they act in ways we have not anticipated. In the context of the Macrogenics platform, we actually don’t know yet, as DART006 is very early in clinical development. BiTEs (Bi-specific T cell Engagers), Micromet’s version of a bi-specific technology, have been around a while and are further advanced. Acute Lymphocytic Leukemia (ALL) patients are now being recruited into Phase 3 clinical trials for blinatumomab, the anti-CD3 x anti-CD19 BiTE, with study completion due in July 2017. Micromet was acquired for 1.2BB dollars in January 2012 by Amgen. At the time Amgen R&D head Roger Perlmutter pointed to the Phase 2 clinical trial results in ALL as driving Amgen’s interest in the technology. Indeed, blinatumomab has produced some remarkable data in ALL. Historically, chemotherapy treated ALL patients had a complete response rate (CR) of about 38% and a median overall survival (OS) of 5 months. Rituximab (anti-CD20) didn’t perform much better than chemo. In the blinatumomab Phase 2 trial of adult relapsed/refractory (r/r) ALL, patients received a continuous IV infusion of blinatumomab for 28 days followed by 14-days off drug. Patients who responded could re-up for 3 more cycles of treatment or proceed to allogeneic stem cell transplantation (HCST). There was a very high rate CR of ~70% and the apparent absence of minimal residual disease (MRD) in many patients. Blinatumomab also impacted overall survival (OS) in ALL, as reported at the American Society of Hematology conference (ASH) in 2012 (Abstract #670). The CR was still 69% with most patients being MRD negative. The OS for responders was 14.1 months while the OS for non-responders was 6.6 months (so median OS = 9.8 months). Thirteen of the 36 patients enrolled were able to receive allogeneic HSCT.

The most common adverse events (AEs) were fever, headaches, tremors, and fatigue. Some patients experienced severe AEs (SAEs) such as cytokine release syndrome (CRS) and central nervous system events, including seizures and encephalopathy. One patient stopped treatment due to fungal infection leading to death. So, there is tox to consider.

A smaller study directed to salvaging patients with MRD despite prior treatments showed even more dramatic results: 16/21 patients became MRD negative and the probability for relapse-free survival was 78% at a median follow-up of 405 days. This is a remarkable result. An SAE led to one drug discontinuation.

Last year at ASH (Abstract #1811) we saw early results from an open label phase 2 study in r/r Non-Hodgkin’s Lymphoma (NHL), specifically, Diffuse Large B cell Lymphoma (DLBCL). Blinatumomab was administered by continuous IV for 8 weeks. Patients received either stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, or received 112 μg/d throughout. All patients received prophylactic dexamethasone. So you can see some dose modifications here designed to reduce SAEs. After a 4-weeks off drug, patients who had responded could receive a 4-week consolidation cycle. 11 patients had been enrolled, 7 patients were evaluable for response. These patients had failed >2 prior therapies, including some patients who had relapsed after HSCT. The overall response rate (ORR) was 57% (14% CR plus 43% partial response (PR); 30% had progressive disease (all from the stepwise dose regimen). Note this is a very small sample size so every patient has a large impact on the response numbers. Ten of 11 patients had at least one grade ≥3 AE with 2 patients having grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no drug related fatalities. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor, speech disorder and disorientation: in 5 patients these CNS toxicities were grade 3. The overall benefit/risk assessment suggested stepwise dosing (9, 28, 112 μg/d) to be the recommended dose.

Well first of all let’s point out here that blinatumomab has orphan drug status for ALL and NHL. That’s just to remind ourselves that these are pretty rare diseases with high unmet need. For ALL in particular this seems a good risk/benefit scenario. Within the diseases that make up NHL, DLBCL is not the most treatable (nor the least), and we note also that there is no attempt in the open-label phase 2 to characterize DLBCL into its subclasses – these have different oncogenic drivers and different outcomes for patients. Blinatumomab has also been in Phase in in other NHL classes, including Mantle Cell Lymphoma and Follicular lymphoma. Response rates were generally below current standard of care. Similarly, we can go back to look at rituximab, ofatumumab, and even ibrutinib, idelalisib and ABT-199 in NHL and likely find better treatment paradigms for r/rDLBCL than this, although maybe not as a monotherapy (see those earlier posts here: http://www.sugarconebiotech.com/?p=16).

Given the modality (CD3 x CD19 bi-specific) maybe the most interesting comparison is with Novartis’ CAR-T CD19 technology CTL019. CTL019 is the product of genetic engineering technology developed by Carl June’s group at U Penn, and is currently advancing in close to 20 clinical trials. The most advanced is a Phase 2 trial in r/r ALL, with a primary outcome completion due in July of 2015. As a quick reminder, CARs combine a single chain variable fragment (scFv) of an antibody (e.g. anti-CD19) with intracellular signaling domains from CD3 and 4-1BB into a single genetically engineered chimeric protein. The CD19-specific version of this technology is termed CTL019. Patient’s T cells are lentivirally transduced with a CAR, expanded ex vivo then infused back into the patient. Infusion of these cells results in 100 to 100,000x in vivo T cell proliferation, anti-tumor activity, and prolonged persistence in patients carrying CD19+ B cell tumors. Results from a pilot study in pediatric and adult r/r ALL were presented at ASH in 2013 (Abstract #67). Most patients received lymphocyte-depleting chemotherapy just a few days prior to infusion. This helps de-bulk the malignancy. In this small trial, 82% achieved a CR, 18% did not respond. Of the patients achieving CR, 20% subsequently relapsed. The rest of the patients are being followed and there has been no update. Responding patients all developed CRS, and about 30% of patients were treated with the IL6-receptor antagonist tocilizumab plus corticosteroids to control CRS symptoms.

We have a little more data on CTL019 from NHL studies, specifically r/r CLL. In December 2013, Phase 2 data were presented at ASH (Abstract #873).  Patients with r/r CLL received lymphocyte depleting chemotherapy and then one of several doses of transduced T cells (this is a dose study in that regard, although, cutting to the chase, no dose response was seen, so lets skip over that). Median follow-up for analysis was 3 months at which time the ORR = 40% (20% CR plus 20% PR, with clearance of CLL from the blood and bone marrow and at least a 50% reduction in lymphadenopathy. The toxicity profile was similar to that described above, dominated by treatable CRS. In a small Phase 1 study (Abstract #168), adult patients with r/r NHL including patients with chemotherapy-refractory primary mediastinal B cell lymphoma and DLBCL were enrolled. They received chemo to reduce disease burden and then an infusion of CTL019. 12 of 13 evaluable patients responded (ORR = 93%), the CR = 54% and PR = 38%. These are outstanding responses.

So let’s take a step back. It is a bit hard to compare these regimens head-to-head as they are in different stages of clinical development, the trails are generally small, and in the case of NHL, we have limited data on different types of lymphomas. At the same time we have to consider the larger landscape of therapies available, and ask ourselves how patients will best be served. In the case of the T cell engaging bispecific antibody landscape, it is very clear that robust anti-tumor responses are generated with very low concentrations of antibody. It seems to me very likely that there will be malignancies or subsets of malignancies where this technology will be very useful, including ALL, as we just saw. It will be important to either improve the antibody construction or alter the dose regimen sufficiently to reduce the toxicities associated with the BiTE therapeutic and competing modalities, including the DARTs. Now, people will claim that the tox is not so bad, and that it is only efficacy that matters, and that’s fine, but in the face of competition from CTL019 and other therapeutics, maybe this becomes a differentiating issue. This might also be different for the pediatric population (a critically important population in ALL) versus the adult population. When we look at the CAR T cell transduction technologies we need longer follow-up on the phase 2 studies but certainly anecdotal evidence from smaller trials suggests that some patients will experience long-lasting remissions. If this observational information holds up in the larger clinical trials than the technology will cement itself a place in ALL therapy, and perhaps in other diseases as well. We don’t know yet whether the BiTE therapeutic blinatumomab or the CAR therapeutic CTL019 will have a top-tier profile in NHL. This may change as more data become available, as some of the small studies are very encouraging. One of the interesting twists to the CAR technology is the question of how to make it widely available. In host-institutions (The U Penn system, MD Anderson, NCI) this is a centralized procedure, and in medical institutions world-wide, core patient cell facilities are commonplace. However it is rumored that Novartis at least wants to maintain the core facility model, as they picked up the Dendreon facility in Morris Plains New Jersey (at a bargain price) specifically to support CAR technology, and plan to duplicate those capabilities in Basel and in Singapore. Perhaps yesterday’s pickup of Israel’s Gamida Cell also plays into this centralized cell handling model. None of these complexities will bother the bi-specific therapeutics as these are injectable – that said, I’m not sure anyone will choose walking around with an IV pump for two months if they can avoid it.

So while these therapies and those like them are very potent, we will have to see how patients and providers ultimately use them.

Now, we’ve unfairly used blinatumomab and CTL019 to illustrate what are both pretty large areas of therapeutic development. We’ll come back to talk about the other players in the bispecific antibody and CAR spaces very soon.

stay tuned.

AML Therapeutics Part 3: Immunotherapy

ADC, Amgen, AML, biologics, CAR-T, chimeric antigen receptors, Lymphomas, Leukemias, Myelomas, Merck, monoclonal antibodies, oncology, Onyx Pharma

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Ryan Teague and Justine Kline recently put together a nice review of immune evasion in acute myeloid leukemia (AML). The open access paper is available online (http://www.ncbi.nlm.nih.gov/pubmed/24353898). These authors have particular interest in tumor escape from immune surveillance by two interesting mechanisms. The first is termed T cell exhaustion, and refers to a non-responsive state induced in CD8+ (cytotoxic) T cells. The second is immune suppression, mediated by TGFbeta and regulatory T cells (Tregs). Other means used by tumor cells to avoid the immune system include deactivation by co-opting signals that directly shut down immune responses, such as PD-1 and other signaling mechanisms.

Why the interest in immunotherapy for such an aggressive cancer? There are a number of good reasons. First I think it is fair to state that targeted therapeutics (small molecule drugs) and antibodies (mAbs, ADCs, bispecifics) have yet to achieve a breakthrough in AML. The best of these drugs, even in combination, are only modestly effective. The second reason, implicitly recognized by the T cell engaging bispecific antibodies (BiTEs, DARTs) and by the still nascent CAR-T cell engineering technology, is that there is evidence to suggest that AML can be controlled by an effective immune response. This evidence comes from the leukemia transplantation field. As Teague and Kline state:

“Treatment with modern chemotherapy regimens often induces complete remission, but a majority of patients will ultimately relapse … it has been recognized that allogeneic stem cell transplantation can be curative for some patients with AML … derived from the so-called graft-versus-leukemia effect thought to result … Unfortunately, only a minority of patients with AML are candidates for this procedure.”

Those who are familiar with allogeneic SCT will further recognize that this is a risky procedure that can outright fail. So, are there safer or more direct ways to harness an anti-tumor immune response?

Novel therapeutics developed to stimulate anti-tumor immunity include the CTLA4 antagonist mAb, ipilimumab (Vervoytm; Bristol Myers Squibb (BMS)), approved for use in refractory or non-resectable melanoma. BMS is also developing the anti-PD1 mAb nivolumab, and combination trials with ipilimumab are underway. Other anti-PD1 and anti-PDL1 antibodies in advanced development for a variety of tumor types include MK-3475, submitted last month for FDA approval for the treatment of advanced melanoma, MPDL3280A (Roche), MEDI4736 (Astra Zeneca), and others. These are critically important therapeutics in hematological cancer and solid tumors. The potential breadth of applications is illustrated by the announcement last week the Merck will seek collaborative partnerships to develop MK-3475 in combination therapies. Merck will partner with Pfizer to investigate combination therapy in a phase 2 renal cell carcinoma (RCC) trial with the VEGFR inhibitor axitinib (Inlytatm). Merck will also partner with Pfizer for a phase 1 trial(s) using MK-3475 with the agonist anti-41BB antibody PF-2566, in multiple cancers. Readers will note that 41BB signaling is a critical component of the CAR-T T cell engineering technology. The collaboration with Incyte is also a dual-immunotherapy approach, as MK-3475 will be combined with INCB24360, an IDO inhibitor, in a phase 1 non-small cell lung cancer (NSCLC) trial. IDO is secreted by tumor cells, is a mediator of T regulatory T cell activity, and in AML is associated with poor prognosis. With Amgen, MK-3475 will be used in combination with the oncolytic viral therapeutic T-VEC, which induces tumor cell death and stimulates anti-tumor immunity.

The point of all this is to illustrate that for difficult cancers – melanoma, RCC, NSCLC – its not going to be easy, and combinations of novel therapeutics will have to be utilized. AML is a very difficult cancer. With this in mind we can look at the state of immunotherapy drug development in AML.

The Teague and Klein review goes into considerable detail on this subject, so we’ll just hit a few highlights and then see if we can update the storyline. A point the review makes that I didn’t fully appreciate is that AML tumor cells (and many others) can downregulate MHC Class I and II, making the tumor cells difficult for the immune system to recognize in the context of allogeneic SCT. This fundamental type of immune evasion may be difficult to circumvent. Other mechanisms of immune evasion used by AML include expression of PD-1L on the tumor cells, which effectively shuts down tumor infiltrating T cells that express PD-1, the PD-L1 receptor and mediator of a potent signaling response that downregulates T cell activity. AML tumor cells also express B7 family proteins B7-1 and B7-2,that bind to CTLA4, another downregulatory receptor. Clinical trials enrolling AML patients for treatment with therapeutics such as ipilimumab, nivolumab etc are described in the review. Its sufficient to point out that the effort to use these therapeutics for AML is in its very earliest stages.

A few recent observations point to other immune evasion strategies that night be productively targeted in AML.

Several preclinical studies have identified co-expression of TIM-3 and PD-1 as markers of CD8+ T cell “exhaustion”, and have likewise identified PD-L1 and galectin-9 (a putative TIM-3 ligand) on AML patient cells. TIM-3 is yet another receptor on T cells that mediates downregulation of T cell activity. Other markers of AML cells from patients were recently described (https://ash.confex.com/ash/2013/webprogram/Paper56968.html).

Relevant proteins included B7-2 (CD86), B7-H3 (CD276) and PD-L1. Patients with very high expression of both B7-2 and PD-L1 had worse overall and relapse free survival. HVEM, a receptor for several critical immune proteins including LIGHT, CD160, and BTLA, was expressed on a subtype of AML with relatively good prognosis. The author’s conclude ” that the profile of immune checkpoint molecules … correlates with molecular disease characteristics in AML and may even possess prognostic information, especially for relapse … (and) as therapeutic targets with respect to boosting anti-leukemic immune responses.”

An example of such an approach is provided by Innate Pharma, which is developing an anti-KIR antibody, lirilumab. KIR negatively regulates NK cell anti-tumor activity. A phase 1 trial in AML is continuing                             (https://ash.confex.com/ash/2013/webprogram/Paper59174.html). Preclinical data support the use of this mAb in combination with the cytotoxic anti-CD20 mAb rituximab in lymphoma. One might envision a similar approach using a cytotoxic mAb targeting AML such as the anti-CD33 mAbs discussed in part 2. Another possibility are the anti-CD38 mAbs. Second generation CD38 mAbs with improved cytotoxic activity are under intensive development for multiple myeloma by Sanofi (mAb SAR650984), Jannsen (daratumumab aka HuMax CD38) and MorphoSys (mAb MOR03087).

Another example is CoStim Pharma, bought today by Novartis. In their portfolio are novel immunotherapeutic mAbs, including TIM-3 antagonist mAbs. Novartis is moving quickly here to beef up its immunotherapeutic pipeline, which it can now develop in parallel with the U Penn CAR-T technology. Another local, private immunotherapy company is Jounce Therapeutics.

As we have also seen in parts 1 and 2, drug development for AML lags significantly behind other leukemias, lymphomas, myelomas, and the like. However, targeted therapeutics such as the tyrosine kinase inhibitor sorafenib, HDAC inhibitors vorinostat and panobinostat, and proteosome inhibitors bortezomib and carfilzomib hold some promise. The FLT3 and c-Kit targeting agents seem less likely to provide meaningful long-term benefit, although we’ll see what the combo trials brings. While it is too early to assess the CAR-T technology, the bispecific modalities, or immunotherapies in AML, the cytotoxic mAbs and ADCs should have a prominent role in controlling this aggressive disease.

We asked in Part 1 who the winners would be in 5 years. Looking over the landscape of therapeutics its pretty clear that winning will require collaboration among companies. With that said those companies with the biggest concentration of effort in AML include Merck, Onyx, Novartis, Amgen and perhaps Seattle Genetics. Given their past successes we can be hopeful that several of these companies will succeed in establishing breakthrough treatments for AML. In the end, patients should benefit the most from all of this activity. Perhaps stockholders will also benefit. With this in mind we note that Onyx probably has the most to gain (or lose) in this indication.

 stay tuned.

Anticipating new therapeutics and forecasting treatment trends for acute myeloid leukemia – Part 2

ADC, AML, biologics, CAR-T, chimeric antigen receptors, Companies - stock symbols, monoclonal antibodies

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Here is a quick recap of Part 1: we looked at some of the targeted small molecule drugs being developed for AML. That class of therapeutics can be binned into logical groups, as follows:

1) pan-signaling pathway inhibitors like sorafenib, sunitinib, even ponatinib

2) drugs that hit c-Kit (and various other receptor tyrosine kinases) like dasatinib and imatinib

3) drugs that target FLT3 (and usually hit other kinases) like quizartinib, midostaurin, lasartinib, and PLX3397

4) proteosome inhibitors like bortezomib and carfilzomib

5) epigenetic modulators like vorinostat, panobinostat, 5-azacitidine, decitabine and entinostat

6) miscellaneous. We discussed several of these in Part 1, and there are many more. One more of interest is AG-221 (Agios; AGIO) that targets the mutated IDH2 gene. IDH1 can also undergo mutation in AML. Such drugs are a nice idea, unlikely to work as monotherapy (just my view), but perhaps useful in combo. AG-221 is currently in early stage clinical development.

In the small molecule drug development landscape there is logic that is readily understandable, and the combinations of drugs being tried make good sense. In contrast the biologics side of AML drug development is pretty haphazard. On the other hand true breakthroughs leading to transformative changes in clinical practice very likely will be found here.

So lets move on to Part 2: Biologics, including cytotoxic monoclonal antibodies, ADCs, bi-specific antibodies, cell based therapy and few odds and ends.

An antibody that illustrates that haphazard nature of AML drug development is gentuzumab, a monoclonal antibody (mAb) directed to CD33, a protein expressed at high levels on AML cells. The mAb was coupled to a calicheamicin derivitive and developed as gentuzumab ozogamicin (GO). GO is therefore an antibody-drug conjugate (ADC). This drug was originally approved as Mylotargtm (Wyeth, now Pfizer; PFE) for the treatment of AML more than a decade ago based on a phase 2 trial data showing a CR + CRp rate of 30%. However the drug showed less benefit than expected in phase 3, plus unanticipated hepatic toxicity, and was pulled off market. GO continues to see use in clinical trials and off-label and has been shown to add to the effectiveness of chemo in AML patients carrying specific cytogenetic markers. A meta-analysis of large phase 3 trials was reported in the Annals of Oncology 2 weeks ago                           (http://annonc.oxfordjournals.org/content/25/2/455.abstract). Data from nearly 3600 patients (half treated, half controls) from five randomized phase 3 trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, P = 0.05) and relapse free survival (HR 0.87, P = 0.003), decreased rates of resistance (OR 0.71, P = 0.01) and relapse (OR 0.75, P = 0.002), but oddly had no effect on CR rate, suggesting that complete response status was disconnected from longer term outcomes (this is actually very common). Subgroup analysis identified cytogenetic status as an important variable for response to GO. On the downside, the risks of grade 3–4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in the GO arm.

Additional analysis is due this spring, and will likely be available at AACR or ASCO.

GO provided clear clinical POC that targeting CD33 could be an effective strategy for AML, and Seattle Genetics (SGEN) had also developed a naked antibody called SGN-33 (lintuzumab) that failed in phase 2b, demonstrating no efficacy benefit compared to chemo alone. Seattle Genetics has therefore developed a second-generation anti-CD33 targeting mAb, as an ADC. The mAb is coupled to pyrrolobenzodiazepine (BPD) a DNA minor groove-binding molecule that effectively stops tumor cell division and induces cell death. The resulting ADC is called SGN-CD33A. A phase 1 trial in AML just got underway (NCT01902329).

A very different mechanism for targeting CD33 is being developed by Amgen (AMGN) using technology acquired when they bought Micromet. Micromet developed a bi-specific antibody technology termed BiTE. BiTE antibodies fuse two single-chain mAbs, one that binds CD3 on T cells and a second that binds tumor cell antigens. The idea is to redirect T cells to selectively lyse tumor cells. AMG330 is a BiTE antibody with CD33 antigen recognition. This therapeutic is still in preclinical development.

A different bispecific modality is BiKE, in which an NK cell targeting mAb (anti-CD16) is coupled to anti-CD33. The idea is to trigger NK cells to degranulate thereby killing the tumor cells. Nice idea, probably a long shot, in preclinical development.

Yet another approach to targeting CD33 has been developed in the context of CAR-T technology. CAR-T technology is based on introducing a tumor-targeting construct to the patients own T cells ex vivo. A lentiviral vector expressing a chimeric antigen receptor with specificity for AML antigen CD33 is coupled with CD137 (4-1BB) and CD3-zeta signaling domains. A low dose of modified T cells are then re-infused into the patient. This technology is dubbed CART-33. The cells rapid proliferate and are activated in the presence of antigen (ie. the tumor cells), inducing a robust and long-lived anti-tumor response. A phase 1/2 trial has begun in Beijing (NCT01864902). We can expect additional trials to be added. This therapeutic approach has worked well in advanced lymphomas (with CD19 as the antigen). The technology, licensed by Novartis, is one to watch very closely.

Finally, radioactively labeled anti-CD33 mAbs have been developed, including conjugates of anti-CD33 mAb M195 to 131-I and 213-Bi. The latter conjugate was run in a Phase 1 trial but the clinical trial literature here is sparse. Other radiolabeled mAbs used for AML treatment include a 131-I-conjugated anti-CD33 mAb BC8 and a Y90-conjugated anti-CD45 mAb. Both are undergoing clinical testing at the Fred Hutchinson Cancer Center, apparently with very promising results. In general, radiolabeled mAbs that emit β-particles, such as I131-anti-CD33, Y90-anti-CD33, and I131-anti-CD45, deliver high doses of radiation to the bone marrow and are used as pre-conditioning prior to SCT. Re188-anti-CD66c also falls in this catagory. Short-ranged α-particle emitters like Bi213 Bi-anti-CD33, are used to treat low-volume or residual disease.

Another company that is using bispecific technology to target AML to activated T cells is Macrogenics (MGNX). They have developed an anti-CD3/anti-CD123 DART mAb MGD006, partnered with Servier. This Dual Affinity Re-Targeting (DART) construct is built from 2 different polypeptides, each comprising the VH of one antibody in tandem with the VL of the other antibody, creating a heterodimer that is stabilized by disulfide binding. This construct binds to both CD123 and to CD3 in the human T-cell receptor complex. A phase 1 trial should begin this year.

CD123 is the IL-3 receptor, expressed on myeloid lineage cells and elsewhere, highly expressed on AML cells. It also is expressed on leukemic stem cells, leading to the hypothesis that targeting CD123 might prevent relapses by eliminating residual tumor progenitor cells from the bone marrow niche. Recent data suggest that mutations in the signaling chain of CD123 may contribute to oncogenesis in some lymphomas and leukemias, including AML. Early POC was provided by the mAb 7G3, which showed potent in vitro and in vivo killing of human AML cells. This mAb did not undergo further development, although it appears occasionally in the radio-immunotherapy literature, e.g. as In-111-NLS-7G3 where NLS is a 13-peptide linker.

An anti-CD123 mAb already in Phase 1 is CSL362, a novel monoclonal antibody therapy. This antibody has been engineered antibody to efficiently recruit NK via the Fc portion of the antibody, so this is a classic antibody-mediated cytotoxicity approach. The mAb is being developed by CSL LLC and is partnered with Janssen.

 Stemline Therapeutics (STML) is developing SL-401, which is comprised of the IL-3 protein conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis. This construct reportedly has anti-tumor potency against tumor cell lines and primary tumor cells in the femtomolar (10-15 M) range. SL-401 is in Phase 2a in AML. That trial should report out preliminary data this year.

Of great interest is the CAR-T technology as applied to CD123 (CART-123). The technology is the same as discussed above for CART-33, and is in preclinical development. Again this is technology developed at U Penn and licensed to Novartis. We won’t get into the competitive landscape of modified T cell technologies, nor the intellectual property wars, a subject perhaps for another time.

A few other biologics to keep an eye on:

– Trebananib (AMG386) is a peptibody targeting the Angiopoietin 1/2 proteins. These are ligands for Tie2, a receptor on endothelial cells that promotes tumor angiogenesis. Peptibodies are petides fused to the Fc domain of an antibody. The peptide provides the parget recognition. A phase 1 reported at ASH that the therapeutic was safe and showed preliminary signs of efficacy in adult AML (Abstract #2710).

– Igenica is a private company that just received Series D funding of 14MM USD to advance IGN523 into the clinic. The funding round was led by Third Rock Ventures. IGN523 is an anti-CD98 antibody that targets both the tumor cells and tumor stem cells. CD98 is the neutral amina acid transported expressed on dividing lymphocytes, and it has been argued that IGN523 functions not only by inducing antibody-mediated cytotoxicity (by NK cells and CD8+ T cells) but also by blocking activity of the receptor.

– CXCR4 has emerged as an attractive target in AML, beyond the standard application of CXCR4 to mobilize stems cells. More recent work has focused on using CXCR4 antagonists like plerixafor (a small molecule) for chemo-sensitization (see ASH 2013 abstract #2680). More direct targeting is being pursued by Bristol Myers Squibb (BMS), with the antibody BMS-936564 (ASH abstract #3882), currently in phase 1 for AML (NCT01120457). Other CXCR4 agents are in development.

– other antigens have been recently identified.

If we look broadly at the biologics being developed for AML a few things jump out. First, there are no home runs, as we have seen in other lymhomas such as Non-Hodgkin’s lymphoma, where the anti-CD20 mAb rituximab showed dramatic response rates early in clinical development. Second, it’s still early for nearly all of these agents, with the exception of the GO ADC. Third, and this is a very common theme, combination therapies will be required to control this brutal disease. We saw in the review of small molecule therapeutics that companies and the NCI are co-sponsoring trials in order to move clinical practice forward, and we should expect similar collaboration as the biologics move ahead (indeed we already see this with the GO combo trial).

Tomorrow we’ll talk about the role of immune-checkpoint therapeutics in AML, a field with great promise.