Monthly Archives: July 2015

“Combination Cancer Immunotherapy and New Immunomodulatory Targets” published in Nature Reviews Drug Discovery

Part of the Article Series from Nature Reviews Drug Discovery, our paper hit the press today

Combination cancer immunotherapy and new immunomodulatory targets. Nature Reviews Drug Discovery 14, 561–584. 2015.  doi:10.1038/nrd4591

by Kathleen Mahoney, Paul Rennert, Gordon Freeman.

a prepublication version is available here: nrd4591 (1)

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.