The Tumor Microenvironment “Big Tent” series continues (part 4)

 
The Tumor Microenvironment (TME) series to date is assembled here http://www.sugarconebiotech.com/?s=big+tent containing parts 1-3
I’m happy to point you to the most recent content, posted on Slideshare: http://www.slideshare.net/PaulDRennert/im-vacs-2015-rennert-v2
In this deck I review the challenges of the TME particularly with reference to Pancreatic and Ovarian cancers. A few targets are shown below.
Feedback most welcome.

 

The Big Tent: Halozyme is Targeting the Tumor Microenvironment, part 3 of an occasional series.

Many drug development programs claim to be truly unique and novel. It’s a mixed message really – complete novelty implies (or ensures) a high level of risk. It’s a bit difficult to attract early investment to such programs and maintain investor interest going forward. When we work with companies raising money, or are raising money ourselves, we are constantly trying to minimize risks, plural, as risks represent diverse aspects of a program or company: technology risk, biology risk, clinical risk, commercial risk, to highlight just a few. Companies that can move novel programs forward while derisking them in multiple areas certainly warrant our attention – for the scientific thesis and the investment thesis. We recently wrote about Innate Pharma, a company with first-in-class programs targeting NK cell immune checkpoint pathways (link 1). This is a good example of a company that has shed biology and clinical risks as the partnership with Bristol-Myers Squibb (BMS) continues to grow. The entire second tier of antibody-drug conjugate linker/payload companies (Redwood, Igenica, Mersana, Catalent and many others) will remain technology risk-heavy until each individual company either secures partnerships that eventually move ADCs into the clinic, or get their themselves. We could go on and on.
A few weeks ago I asked for companies and programs targeting the tumor microenvironment. Among the responses I got these:

Halozyme (Nasdaq: HALO) has a lead program that is very novel and I think scientifically is very interesting and has understood biological risk. We’ll talk about other risk elements in a bit, but science first. PEGPH20 is a pegylated version of the company’s approved recombinant human hyaluronidase (rHuPH20; brand name Hylenex). Hylenex is licensed to several partners, and provides a steady income stream from royalties. Hyaluronidase catalyzes the random hydrolysis of 1,4-linkages between 2-acetamido-2-deoxy-b-D-glucose and D-glucose residues in hyaluronan (HA), a constituent …

The Big Tent: Tumor Microenvironment Targets Heat Up – part 2 of an occasional series

I recently asked folks for their favorite hot targets in the tumor microenvironment space. Among a flurry of responses I got these two related answers:

 

These responses from @mcbio316 and @Festivus159 were very timely, given what happened 4 days later (and a big shout-out to mcbio, whose post had preceded this):

Bristol-Myers Squibb and Five Prime Therapeutics Announce Exclusive Clinical Collaboration to Evaluate the Combination of Investigational Immunotherapies Opdivo (nivolumab) and FPA008 in Six Tumor Types

Five Prime Therapeutics, Inc. November 24, 2014 8:59 AM GlobeNewswire

NEW YORK and SOUTH SAN FRANCISCO, Calif., Nov. 24, 2014 (GLOBE NEWSWIRE) – Bristol-Myers Squibb Company (BMY) and Five Prime Therapeutics, Inc. (FPRX) today announced that they have entered into an exclusive clinical collaboration agreement to evaluate the safety, tolerability and preliminary efficacy of combining Opdivo (nivolumab), Bristol-Myers Squibb’s investigational PD-1 (programmed death-1) immune checkpoint inhibitor, with FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R). The Phase 1a/1b study will evaluate the combination of Opdivo and FPA008 as a potential treatment option for patients with non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, pancreatic cancer, colorectal cancer and malignant glioma. Bristol-Myers Squibb has proposed the name Opdivo, which, if approved by health authorities, will serve as the trademark for nivolumab.

So BMS will immediately move FPA008, but all measures an early stage and largely unproven therapeutic, into combination therapy trials with nivolumab for the treatment of solid tumors. Not to be outdone, Roche has already positioned it’s CSF1R targeted therapeutic, as noted by @jq1234t:
 

There are a number of interesting questions to answer here: What does CSF1R do, why is it so interesting, how does it impact the tumor microenvironment, how are these trials being done and (a favorite of mine), who else has assets in development?

CSF1R is the receptor for macrophage-colony-stimulating factor (aka M-CSF or CSF-1). The receptor is a control …

The Tumor Microenvironment – A Big Tent

 We have talked repeatedly about the promise of immuno-oncology, and with good reason. Very recent data show that the landscape of cancer care is changing rapidly and dramatically for the better. We continue to see contributions from diverse therapeutic modalities: immune checkpoint modulation, novel antibodies, bispecifics, CAR T therapy, TCR therapy and others. Massive amounts of resources have poured into this space, and interesting new companies continue to launch in the Boston area: Surface, Unum, Potenza, Enumeral to name just a few.

The last decade has seen intense focus on the immune checkpoint field, and clinical development in that space is encompassing combination therapy as the defining principal to advance treatment (Mahoney et al. NRDD, submitted). While much of the effort is driven toward combining antagonists of T cell immune checkpoints (CTLA4, PD-1, TIM-3, etc) with T cell activators (4-1BB. OX40, CD27, etc), this approach may be self limiting due to the toxicity associated with hyper-activation of T cells (cf. CAR Ts and BiTES) alongside the limitation of targeting just one arm of the immunosuppressive armature deployed by tumors.

Further, we understand that affecting outright cures in more patients is a dramatic step change, and we are not there quite yet, outside of hematology perhaps. It is obvious (we think) that curing cancer will require taking down the infrastructure that supports tumor cell survival, proliferation, resistance and metastasis. For solid tumors and niche-homing leukemias/lymphomas this infrastructure is built on the foundation of tumor cell/stroma interaction, where we define the stroma as extracellular matrix and associated cells – tumor associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), tumor associated fibroblasts, endothelium, other mesenchymal-lineage cells, etc. The composition may vary from indication to indication, with more or less complexity.

Let’s set the stage using three biology buckets:
 

Immuno-oncology focuses intently on tumor cells and tumor-expressed antigens, and …

Angst in the IO Combo field – part 2 (lessons from #AACR17)

I posed this question regarding IO combinations in the last post, leading up to AACR:
“Why the perception of angst then? The sentiment has been summed up as “everything will work a little, so what do we research/fund/advance? How do we choose? How will we differentiate”?
I was mulling over these questions as I prepared remarks for Jefferies Immuno-oncology conference – the slides below are taken from the deck I presented.
Even the comment “everything will work a little” now seems to be an overreach. We could instead say: “most combinations won’t work at all”, meaning they won’t work better than anti-PD-1/PD-L1 monotherapy or anti-CTLA4 monotherapy, or, that they won’t work better than those therapies used in combination with standard of care.
Remember two years ago? We were going to take an anti-PD-1 to “release the brake” and add anti-4-1BB or anti-OX40 to “step on the gas”. While it is still early, this seems to be an empty paradigm. Why? Certainly the 4-1BB and OX40 pathways are intensely potent when used to drive T cells directly (e.g. anti-CD3 + anti-4-1BB in vitro or as used in a CAR-T cell). Is it too early to tell? Have the wrong patients been enrolled in trials? Are the antibodies no good? Is it the Fc? IS THE TUMOR COLD?
So here we go, onto the next paradigm, summed up in the phrase “make cold tumors hot”. What happened to stepping on the gas?
At AACR, Dan Chen (from Genentech, a Roche company) laid out the case for using not 1, not 2, not 3, not 4, not 5 … but up to 11 different therapeutics to successfully treat a given tumor – he exaggerated to make the point that none of the current immune checkpoint inhibitors (ICIs) should be expected to work in synergy with anti-PD-1 therapy, a priori. Why …

CAR T updates – tangled tales unwound

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

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

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

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

So now I’ve gone through the abstracts presented at AAAS and some of the primary literature, and I’ve a Cliff Notes version of what data were actually presented and what the data mean and don’t mean. I seems clear that the confusion regarding the results arose from the oversimplified weaving of two talks (by Dirk Busch …

The Tumor Ecosystem: some thoughts stirred up at the NY International Immunotherapy meeting

Ecosystems in tumor immunity
The buzzword ‘ecosystem’ has popped like a spring dandelion, and it is now used everywhere in biotech. I’m as guilty as anyone of rapid adoption: the term does capture essential elements of modern biomedical science. Complex and interlaced, with key control nodes at work at all levels – scientific, financial, clinical, commercial – and also dynamic, constantly driving adaptation, and, we hope, innovation. Scientifically the ecosystem connections are easily spotted. CRISPR technology appears in cellular therapies including TCRs and CAR-Ts as we simultaneously learn that the mechanisms of immune checkpoint suppression deployed by tumor cells can derail genetically engineered CAR T cells as readily as normal T cells. Further, those genetically engineered CAR T cells and TCRs owe their existence in large measure to our newly developed ability to sequence tumors at the individual level, with great sensitivity, to identify novel targets. The whole enterprise in turn requires ever faster, cheaper, smaller and more reliable equipment (RNA spin columns and PCR cyclers and cloning kits and desktop sequencers and on and on) and software to handle the data. Enterprises like these in turn drive discovery and innovation.
Within the tumor is another ecosystem – the tumor microenvironment or TME. While TME is a fine term it does blur the notion that this microenvironment is in nearly all cases part of a larger environment and not a walled-off terrarium (perhaps primary pancreatic cancer is an exception, within its fibrous fortress). The tumor ecosystem is a more encompassing term, allowing for the ebb and flow of vastly different elements: waves of immune cells attempting attack, dead zones of necrotic tissue being remodeled, tendrils of newly forming blood vessels, a fog of lactate, a drizzle of adenosine, energy, builders, destroyers, progenitors, phagocytes, parasites, predators. When viewed this way we might wonder …

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 …

Celgene and friends…

The ever-nimble company Celgene (NASDAQ: CELG) was back in the news last week, signing a sweetheart deal with AstraZeneca (NYSE: AZN) that brings access to a Phase III immune checkpoint therapeutic.
The deal between Celgene and Astra Zeneca is remarkable for balancing the relative strengths and weaknesses of each company. For AZN the deal enhances the competitive reach of the anti-PD-L1 mAb MEDI4736, now backed by a rich war chest and the potential for combination therapy with Celgene’s myeloma and hematologic malignancy portfolio. Notably, these diseases have remained relatively indifferent to monotherapy with immune checkpoint therapeutics, with a few exceptions. Refractory multiple myeloma, an indication that Celgene dominates, is particularly resistant to monotherapy with immune checkpoint therapeutics and the bet is that efficacy will be seen when MEDI4736 is paired with Celgene’s approved drugs lenalidomide and pomalidomide, among others. The deal may also ultimately bring access to first line solid tumor patients in the form of a MEDI4736 combination with Celgene’s Abraxane, a synergy that has been overlooked I think.
For Celgene this is an overdue move into the immunotherapy space and reflects their willingness to spend their way into contention and expand market dominance from multiple myeloma into other hematological malignancies, a counter of sorts to Abbvie’s buyout of Pharmacyclics and it’s B cell cancer blockbuster Imbruvica. Celgene has already made forays into the immuno-oncology space with it’s in-licensing of Inhibrx’ anti-CD47 antibody and the deal with VentiRx and Array Biopharma to develop VTX-2337, a TLR8 agonist but these are much earlier stage assets. It is reasonable to predict that Celgene will also move quickly to acquire additional assets in the immune checkpoint space.
I’d expect to see both AZN and Celgene aggressively pursue additional deals. AZN did exactly that with Juno Therapeutics (combining CAR T and anti-PD-L1 therapies) and Innate Pharma in …

Tumor Neo-Epitopes

I’m asked a lot about the onco-vaccine field, and if immune checkpoint inhibitors will be the key to unlocking the potential of this long-suffering therapeutic class. The answer is never simple, since we are often looking at thin patient data that can contain compelling hints of efficacy – those immunized late-stage patients who not only regressed but stay in remission, month after month and year after year. The problem for companies and investors is that such observational data can be very misleading, and the vaccine candidates most often go on to fail in later and larger clinical trials, sometimes spectacularly. These big failures burden the field with a high evidentiary bar.

Data have emerged that suggest several issues with most vaccines, and these issues are both distinct and related.

At the end of November Nature published two interesting papers that asked a very simple question: what immunogenic antigens are present in common mouse tumor models. Yadav et al from Genentech and Immatics Biotechnologies (link 1) used a genome-wide exome and transcriptome sequence analyses, mass spectrometry and structural modeling to identify immunogenic neo-antigens in the widely used MC-38 and TRAMP-C1 mouse syngeneic tumor models. These models are considered poorly immunogenic in wild-type syngeneic (C57Bl6) mice. The sequencing analysis was used to identify mutated proteins that were present at >20% allelic frequency. From the MC-38 model, 1290 expressed mutations were identified of which 170 were considered to be neo-epitopes, that is, modeling suggested they would be expressed by MHCI and sufficient residues would be solvent exposed to allow immunogenicity. Only 67 expressed mutations were found in the TRAMP-C1 model, and of these 6 were considered to be potential neo-epitopes. Of this total of 170 (MC-38) and 6 (TRAMP-C1) only 6 bound MHC1 by Mass Spec, with a predicted IC50 for MHCI < 500nM. Of …