Category Archives: CAR T

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

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.

How far can a CAR get you?

The publication of a paper from scientists at Cellectis (NASDAQ: CLLS) got me thinking. Here is a company with a very interesting idea – to engineer “universal” off-the-shelf CAR T cells by using gene-editing techniques to knock out the elements of an allogeneic T cell that would render it visible to the host immune system. The result – an immunologically “quiet” CAR T cell that you could give to any patient needing the treatment. Sounds good I think. Two things though:

FIRST, some definitions.

A CAR T cell is typically a cancer patient-derived T lymphocyte that is genetically engineered to express a hybrid molecule on its cell surface that can both recognize and then signal the destruction of a cancer cell. The T lymphocyte is most often a cytotoxic T cell (Greek: ‘cyto’ is cell; ‘toxic’ is poison) so this equals a T cell that kills other cells that it sees as foreign to the body with poisons. Cytotoxic T cells express CD8 and can be recognized due to this expression (more on this later).

Gene editing is the use of various technologies to edit (remove in this case) specific genetic elements within a cell (or an organism, a topic for another day). Techniques of interest include those using elements of TALEN, CRISPR or ZFN gene-editing systems.

Allogeneic (Greek: ‘allo’ is other, ‘geneic’ is race) literally means a foreigner, of another race, and biologically means: “denoting, relating to, or involving tissues or cells that are genetically dissimilar and hence immunologically incompatible, although from individuals of the same species”.

So now we understand that what Cellectis is proposing is to genetically alter allogeneic CAR T cells so that, although they are foreign to the patient, they will not be recognized and eliminated. So, “off-the-shelf”, universal, CAR T cells, ready to use. But…

SECOND, to quote a friend of mine: What Problem Are We Solving? In other words, while all of these layers of technology that Cellectus is implementing sound very impressive and appealing, of what utility will they be? Do they address a fundamental and intractable issue in the CAR T field? Should we be excited? Perhaps.

We can step back and ask of the CAR T field: what problems does it have? There are several and they are well known.

1) CAR T cells must be highly selective for the target cancer to avoid unwanted killing of other cells, tissues, organs

2) CAR T cells must proliferate and persist once injected into the patient (i.e. in vivo)

3) Since most CAR T technologies are based on a personalized medicine approach – your cancer attacked by your engineered T cells – there is a fair amount of cell culture to do between harvesting your T cells, altering them (via retroviral or other cell transduction technique), expanding those altered T cells so there are enough to “take” upon injection back into the patient. All of this is expensive, with a typical guess at the price tag of 500K USD

4) CAR T therapy is dangerous (although a bit like Formula One racing – very dangerous and just barely controlled). The danger comes from the potential for off-tumor cell killing but also from tumor lysis syndrome, which happens when large numbers of tumor cells are suddenly killed – all sorts of cellular signals get released and this causes an intense and systemic physiological breakdown – very dangerous, but controllable in an appropriate intensive care unit (so recovery care is also very expensive)

5) CAR T therapy to date has had limited success outside of refractory acute lymphocytic leukemia (ALL). Now, while refractory ALL is a poster child of an indication – intensely difficult to treat, with many pediatric patients – there are about 4000 such patients in the US each year. Commercially, this is limiting.

6) Cancer-specific targets suitable for CAR T technology are very rare.

OK, back to Cellectis, whose lead product targets … refractory ALL. So, what problem are they solving? According to company messaging – control over costs by eliminating the personalzed aspects of the therapy. But we’ve already noted that, right now, that is only one of the critical issues facing CAR T cell technology. That may be enough to grab a piece of the refractory ALL market (and some other indications), and drive valuation for a few years, but a sustainable business, hmmm.  And that we see here is true of all of the CAR T cells targeting the refractory ALL antigen, CD19. Refractory ALL is not a big enough pie for everyone, nor are the niche indications lumped under the non-Hodgkin Lymphoma label, like Diffuse Large B cell lymphoma and Follicular Lymphoma. CAR T companies will get a portion of these patients,  but that will not sustain an industry with a dozen big players. So Cellectis will need more. Of course Cellectis knows this and is looking well past this near term application.

What else happened last week? On the heals of it’s billion dollar 10 year deal with Celgene, JUNO announced the initiation of a CAR T clinical trial employing the impressive sounding “Armoured CAR”. While the term plays nicely to our adolescent/aggressive-minded car culture, what does it actually mean, and, again, what problem are they solving? The armoured CAR T cell is not so much armoured as it is accessorized, carrying a pro-inflammatory cytokine called IL-12 that it expresses as it circulates around the patient looking for tumor cells to kill. Once it finds the tumor, or tumor metastases, the CAR T cell does its usual work, secreting poisons (perforin, granzymes, cytokines, etc) but now, in addition, secreting IL-12, which can amplify the immune response to the tumor via its effects on nearby T and natural killer (NK) cells, including induction of IFN-gamma, enhancement of cell-mediated cytotoxicity and cell proliferation. This approach may work to unlock one of the biggest issues confronting CAR T cell companies – getting solid tumors (as opposed to the “liquid” leukemias and lymphomas) to respond to CAR T therapy at all. So far the results have been disappointing, possibly because the solid tumor microenvironment is so darn immunosuppressive. The JUNO trial is targeting the ovarian cancer antigen MUC16 and will be run at partner hospital, MSKCC. While MUC16 is strongly expressed in ovarian carcinoma (and also pancreatic cancer) the literature indicates normal expression on diverse epithelial cells, including in the lung, the lining of eye and elsewhere. For this reason, as well as the threat of tumor lysis syndrome, JUNO’s armoured CAR also has a off switch that can be activated in case of toxicity. So we are rolling the dice here. Why? Ovarian carcinoma is a large indication with enormous unmet medical need, and pancreatic equally so. Improving patient outcomes in these large and difficult indications would be very notable, and of course, very good business.

Lets look at some data on CAR antigens:

LIST OF SOME ANTIGENS FOR HEMATOLOGIC CANCERS

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THIS SHORT LIST IS REFLECTED IN ONGOING COMPANY-SPONSORED CLINICAL TRIALS

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ACADEMIC CENTERS ARE AHEAD OF THE CURVE, AS IS ALWAYS TRUE IN THIS FIELD

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BUT EVEN HERE, LEUKEMIA AND LYMPHOMA TARGETS DOMINATE (CD19, CD20, CD30, KAPPA Ig, BCMA, ETC)

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AS OF 2014, CD19 TRIALS DOMINATED CLINICAL WORK IN HEMATOLOGIC MALIGNANCIES

THE SOLID TUMOR ANTIGEN FIELD IS SIMILARLY CONSTRAINED

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AND ANOTHER PAGE BELOW

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ALTHOUGH THE DISTRIBUTION OF TRIALS/ANTIGEN IS MORE EVEN, THE NUMBER OF PROTOCOLS IS SMALL (AS OF DATE OF THE REFERENCED PUBLICATION)

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So my hope is that we can engineer CAR T cells with sufficient machinery to “rescue” CAR T technology from the reality of an antigen-poor landscape. The technology is stunning, but I wonder if in the face of such challenges one ought not to look around, and perhaps take another approach. As it turns out, nearly all cellular therapy companies that have taken on the CAR T field have begun to diversify - we’ve been asking what problems we are solving with these clever twists on the basic technology – and this is well worth pursuing. However in the face of a limited pool of targets, lets perhaps consider a technology with a much much larger target list: tumor neoantigens as recognized by T Cell Receptors (TCR). TCR and TIL technologies offer some interesting solutions, and their own unique challenges…

stay tuned.