Category Archives: oncology

Radical optimism: considering the future of immunotherapy

I wrote recently about the sense of angst taking hold in the next-generation class of immuno-therapeutics – those targets that have come after the anti-CTLA4 and anti-PD-(L)-1 classes, and raised the hope that combination immunotherapy would broadly raise response rates and durability of response across cancer indications.

There are diverse next-generation immuno-therapeutics including those that target T cells, myeloid cells, the tumor stromal cells, innate immune cells and so on. A few examples are given here (and note that only a few programs are listed for each target):

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There are of course many other therapeutic targets – OX40/CD134, Glutaminase, ICOS, TIM-3, LAG-3, TIGIT, RIG-1, the TLRs, various cytokines, NK cell targets, etc.

In the last year – since SITC 2017 – there has been a constant stream of negative results in the next generation immuno-therapy space, with few exceptions. Indeed, each program listed in the table has stumbled in the clinic, with either limited efficacy or no efficacy in the monotherapy setting or the combination therapy setting, typically with an anti-PD-(L)-1 (ie. an anti-PD-1 or an anti-PD-L-1  antibody). This is puzzling since preclinical modeling data (in mouse models and with human cell assays) and in some cases, translation medicine data (eg. target association with incidence, mortality, or clinical response to therapy), suggest that all of these targets should add value to cancer treatment, especially in the combination setting. I’ve discussed the limitations of these types of data sets here, nonetheless the lack of success to date has been startling.

With SITC 2018 coming up in a few days (link) I think it is a good time to step back and ask: “what are we missing?”

One interesting answer comes from the rapidly emerging and evolving view of tumor microenvironments (TME), and the complexity of those microenvironments across cancer indications, within cancer indications and even within individual patient tumors. TME complexity has many layers, starting with the underlying oncogenic drivers of specific tumor types, and the impact of those drivers on tumor immunosuppression. Examples include activation of the Wnt-beta catenin pathway and MYC gain of function mutations, which mediate one form of immune exclusion from the tumor (see below), and T cell immunosuppression, respectively (review). In indications where both pathways can be operative (either together or independently, eg. colorectal cancer, melanoma and many others) it is reasonable to hypothesize that different strategies would be needed for combination immuno-therapy to succeed, thereby producing clinical responses above anti-CTLA4 or anti-PD-(L)-1 antibody treatment alone.

A second and perhaps independent layer of complexity is TME geography, which has been roughly captured by the terms immune infiltrated, immune excluded, and immune desert (review). These TME types are illustrated simply here:

Screen Shot 2018-11-05 at 8.45.19 PM

The different states would appear to be distinct and self-explanatory: there are immune cells in the tumor (infiltrated), or they are pushed to the periphery (excluded), or they are absent (desert). The latter two states are often referred to as “cold” as opposed to the “hot” infiltrated state. It is common now to propose as a therapeutic strategy “turning cold tumors hot”. The problem is that these illustrated states are necessary over-simplifications. Thus, immune infiltration might suggest responsiveness to immune checkpoint therapy with anti-PD-(L)-1 antibodies, and indeed, one biomarker of tumor responsiveness is the presence of CD8+ T cells in the tumor. But in reality, many tumors are infiltrated with T cells that fail to respond to immune checkpoint therapy at all. The immune excluded phenotype, alluded to above with reference to the Wnt-beta catenin pathway, can be driven instead by TGF beta signaling, or other pathways. The immune desert may exist because of active immune exclusion, lack of immune stimulation (eg. MHC-negative tumors) or because of physical barriers to immune infiltration. Therefore, all three states represent diverse biologies within and across tumor types. Further, individual tumors have different immune states in different parts of the tumor, and different tumors within the patient can also have diverse phenotypes.

There are yet other layers of complexity: in the way tumors respond to immune checkpoint therapy (the “resistance” pathways, see below), the degree to which immune cells responding to the tumor cells are “hardwired” (via epigenetic modification), the metabolic composition of the TME, and so on. Simply put, our understanding remains limited. The effect of this limited understanding is evident: if we challenge tumors with a large enough immune attack we can measure a clinical impact – this is what has been achieved, for example, with the anti-PD-(L)-1 class of therapeutics. With a lesser immune attack we can see immune correlates of response (so something happened in the patient that we can measure as a biomarker) but the clinical impact is less. This is what has happened with nearly all next-generation immuno-therapeutics. As a side note, unless biomarker driven strategies are wedded to a deep understanding of specific tumor responsiveness to the therapeutic they can be red herrings - one example may be ICOS expression, although more work is needed there. Understanding specific tumor responsiveness is critical regardless of biomarker use, due to the layered complexity of each indication, and even each patient’s tumors within a given indication.

So why should we be optimistic?

I propose that some of the next generation immuno-therapeutics will have their day, and soon, due to several key drivers: first, for some of these classes, improved drugs are moving through preclinical and early clinical pipelines (eg. A2AR, STING). Second, the massive amount of effort being directed toward understanding the immune status of diverse tumors ought to allow more specific targeting of next generation immuno-therapeutics to more responsive tumor types. The TGF beta signature presents a particularly interesting example. Genentech researchers recently published signatures of response and resistance to atezolizumab (anti-PD-L1) in bladder cancer (link). In bladder cancer about 50% of tumors have an excluded phenotype, and about 25% each have an immune infiltrated or immune desert phenotype. The response rate to treatment with atezolizumab was 23% with a complete response rate of 9% (note that responses did not correlate with PD-L1 expression but did correlate with both tumor mutational burden and a CD8+ T cell signature). Non-responding patients were analyzed for putative resistance pathways. One clear signature of resistance emerged – the TGF beta pathway, but only in those patients whose tumor showed the immune excluded phenotype. The pathway signature was associated with fibroblasts, but not myeloid cells, in multiple tumor types. The T cells were trapped by collagen fibrils produced by the fibroblasts:

Screen Shot 2018-11-05 at 9.04.16 PM

(The image is a screenshot from Dr Turley’s talk at CICON18 last month).

It follows that a combination of a TGF beta inhibitor and a PD-(L)-1 inhibitor for the treatment of bladder and perhaps other cancers should be used in patients whose tumors show the immune excluded TME phenotype, and perhaps also show a fibroblast signature in that exclusion zone. Indeed, in a recent paper, gene expression profiling of melanoma patients was used to demonstrate that a CD8-related gene signature could predict response to immuno-therapy – but only if the TGF beta signature was low (link).

There are other immunotherapy resistance pathways – some we know and some are yet to be discovered. We should eventually be able in future to pair specific pathway targeting drugs to tumors whose profile includes that pathway’s signature – this has been done, retrospectively, with VEGF inhibitors and anti-PD-(L)-1 therapeutics. This will require a more comprehensive analysis of biopsy tissue beyond CD8+ T cell count and PD-1 or PD-L1 expression – perhaps immunohistochemistry and gene transcript profiling – but these are relatively simple technologies to develop, and adaptable for a hospital clinical lab settings. Not every next generation immuno-therapeutic will succeed as the clinical prosecution becomes more targeted, but some certainly will (we might remain hopeful about adenosine pathway inhibitors, STING agonists, and oncolytic virus therapeutics, to name a few examples).

Another driver of success will be cross-talk with other technologies within immuno-oncology – notably cell therapy (eg. CAR-T) and oncolytic virus technologies. We have already seen the successful adaptation of cytokines, 4-1BB signaling, OX40 signaling and other T cell stimulation pathways into CAR T cell designs, and the nascent use of PD-1 and TGF beta signaling domains in cell therapy strategies designed to thwart immuno-suppression (we should note here that CAR T cells, like tumor infiltrating T cells, will face  barriers to activity in different tumor indications). The example of local (and potentially safer) cytokine secretion by engineered CAR-T cells has helped drive the enormous interest in localized cytokine technologies. Most recently, the combination of CAR-T, oncolytic virus and immune checkpoint therapy has shown remarkable preclinical activity.

SITC 2018 – #SITC18 on Twitter – will feature sessions on  immunotherapy resistance and response, the tumor microenvironment, novel cytokines and other therapeutics, cell-based therapies, and lessons from immuno-oncology trials (often, what went wrong). We can expect lots of new information, much of it now focused on understanding how better to deploy the many next generation immuno-therapeutics that have been developed.

So, I would argue that “radical optimism” for next generation immunotherapy and immunotherapy combinations is warranted, despite a year or more of clinical setbacks. Much of the underlying science is sound and it is targeted clinical translation that is often lagging behind. Progress will have to come from sophisticated exploratory endpoint analysis (who responded, and why), sophisticated clinical trial inclusion criteria (who to enroll, and why) and eventually, personalized therapeutic application at the level of the indication and eventually the patient.

In the meantime, stay tuned.

Novel Immunotherapeutic Approaches to the Treatment of Cancer: Drug Development and Clinical Application

Our new immunotherapy book has been published by Springer:

http://www.springer.com/us/book/9783319298252

I want to take a moment to acknowledge the stunning group of authors who made the book a success. I’d also like to promote our fund raising effort in memory of Holbrook Kohrt, to whom the volume is dedicated – 5% of net sales will be donated by me, on behalf of all of our authors, the the Cancer Research Institute in New York. So please consider buying the book or just the chapters you want (they can be purchased individually through the link given above.

Now, the authors:

from Arlene Sharpe and her lab (Harvard Medical School, Boston):

Enhancing the Efficacy of Checkpoint Blockade Through Combination Therapies

from Taylor Schreiber (Pelican Therapeutics, Heat Biologics):

Parallel Costimulation of Effector and Regulatory T Cells by OX40, GITR, TNFRSF25, CD27, and CD137: Implications for Cancer Immunotherapy

from Russell Pachynski (Washington University St Louis) and Holbrook Kohrt (Stanford University Medical Center)

NK Cell Responses in Immunotherapy: Novel Targets and Applications

from Larry Kane and Greg Delgoffe (University of Pittsburgh School of Medicine):

Reversing T Cell Dysfunction for Tumor Immunotherapy

from Josh Brody and Linda Hammerich (Icahn School of Medicine, Mt Sinai, NYC)

Immunomodulation Within a Single Tumor Site to Induce Systemic Antitumor Immunity: In Situ Vaccination for Cancer

From Sheila Ranganath and AnhCo (Cokey) Nguyen (Enumeral Inc, Cambridge MA)

Novel Targets and Their Assessment for Cancer Treatment

From Thomas (TJ) Cradick, CRISPR Therapeutics, Cambridge MA):

Cellular Therapies: Gene Editing and Next-Gen CAR T Cells

From Chris Thanos (Halozyme Inc, San Diego) and myself:

The New Frontier of Antibody Drug Conjugates: Targets, Biology, Chemistry, Payload

and a second topic covered by Chris Thanos (Halozyme):

Targeting the Physicochemical, Cellular, and Immunosuppressive Properties of the Tumor Microenvironment by Depletion of Hyaluronan to Treat Cancer

and finally, my solo chapter (and representing Aleta Biotherapeutics, Natick MA and SugarCone Biotech, Holliston MA):

Novel Immunomodulatory Pathways in the Immunoglobulin Superfamily

Please spread the word that all sales benefit cancer research and more specifically, cancer clinical trial development and execution through the Cancer research Institute, and as I said, consider buying the book, or the chapters you want to read.

cheers-

Paul

International Cancer Immunotherapy Conference, quick take: tumor antigens

The sessions yesterday were dominated by discussions of the role of tumor mutations in driving anti-tumor immunity. Tumor mutations can be abundant or rare depending on the indication, and this has an impact on the utility of anti-immune checkpoint therapeutics, as one example. But the question of tumor immunogenicity – can the immune system “see” the tumor – touches multiple therapeutic modalities, among them cellular therapies (TIL and engineered TCR-T cells) and the tumor vaccine field.

Two themes emerged that were not readily compatible. One theme, elegantly on display in the talk by Dr Rosenberg (NCI), is how rare and unique immune activating tumor mutations actually are, when you query patient tumors (or peripheral blood cells) for T cells that can respond to identified tumor mutations. The biology is complex, involving both CD4+ and CD8+ T cells (and the corresponding antigen recognition machinery) on the one hand and variable HLA haplotypes for peptide expression on the other hand. Only when the peptide/MHC (I or II) complex can be recognized by the TCR on a CD4 or CD8 cell can the T cell productively respond. Dr Rosenberg presented analyses of diverse tumor types, making the argument that tumor mutations that can induce T cells responses (thus tumor neoantigens), are unique across patients even within the same indication. Therefore he reasoned that expanding tumor infiltrating lymphocytes (TIL) derived from tumors (using specific cell surface markers) would give one the best chance of finding the right T cell reactivity – after all, that’s why the T cells are within the tumor. Dr Rosenberg has shown very impressive clinical results obtained exploiting these TIL. Such work may also inform efforts by cellular therapeutic companies that use TIL or TCR technology (Lion Bio, Kite, Juno etc).

A different theme emerged later in the session, focusing not on rare tumor antigens but rather on more common tumor antigens. Talks by Dr Sahin (Univ Mainz and BIONTECH Inc) and Dr Rammensee (Univ Tubingen) fell firmly in this camp, with the effort focussed on methods to identify neoantigens that could serve as vaccine components. Much of this work was preclinical, but also some interesting technology validation and early clinical application. This work has broad implications for the tumor vaccine field and perhaps the cell therapeutic modalities, as mentioned above.

So, these two themes clash over the concept the tumor neoantigens are either rare, or more common. This is a puzzle. As always, the details matter. In discussion over dinner, Taylor Schreiber, Anil Goyal and George Fromm from Heat Biologics and Amit Chaudhuri from Medgenome offered possible reasons for the discrepancies:

1) Cell selection – different methods were used to identify the specific populations of T cells to study

2) Antigen analysis – different methods were used to characterize tumor mutations and putative tumor neoantigens

3) Different algorithms – some bioinformatics tools may miss some mutations based on how they distinguish signal from noise (the cancer/testis families were offered as an example here)

So, time to go back and reread the literature.

stay tuned

SugarCone Biotech will be at the International Cancer Immunotherapy Conference: Translating Science into Survival 2015

Paul Rennert, Founder & Principal of SugarCone Biotech LLC, will be attending the joint CRI/AACR event: International Cancer Immunotherapy Conference: Translating Science into Survival 2015. SugarCone Biotech LLC is a consulting firm specializing in biotech strategy and investment.

The conference is in NYC Sept 16-19 and promises to be the key immunotherapy meeting of the fall conference season. Please reach out to connect with Paul at rennertp@sugarconebiotech.com.

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SugarCone Biotech will be at Sach’s Biopartnering 2015

Sach’s is a premier international biopartnering event, a highly focused 2-day conference spanning multiple disciplines and therapeutic modalities. Paul Rennert, Founder & Principal of SugarCone Biotech LLC, will be in attendance, to introduce novel programs and companies to interested investors, and conversely, to connect up and coming biotechs and academic spin-outs to the investment community. Please reach out to Paul during the conference using the one-on-one meeting app or via rennertp@sugarconebiotech.com.

We hope to see you there. Here is the conference web site:

http://www.sachsforum.com/15th-annual-biotech-in-europe-forum-for-global-partnering–investment-29-30-september-2015-congress-center-basel.html

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“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)

#ASCO15

ASCO 2015 is just weeks away and it’s time to get the calendar straightened out. This will be a busy and exciting meeting, and chaotic as always.

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If you would like to meet at ASCO please contact me ASAP at rennertp@sugarconebiotech.com. I love discussing what we do, how we do it, and will happily explain our outstanding breadth of expertise and remarkably synergistic interactions with the biotech, pharma and investor communities. 

Some Adjacencies in Immuno-oncology

Some thoughts to fill the space between AACR and ASCO (and the attendant frenzied biopharma/biotech IO deals).

Classical immune responses are composed of both innate and adaptive arms that coordinate to drive productive immunity, immunological expansion, persistence and resolution, and in some cases, immunological memory. The differences depend on the “quality” of the immune response, in the sense that the immunity is influenced by different cell types, cytokines, growth factors and other mediators, all of which utilize diverse intracellular signaling cascades to (usually) coordinate and control the immune response. Examples of dysregulated immune responses include autoimmunity, chronic inflammation, and ineffective immunity. The latter underlies the failure of the immune system to identify and destroy tumor cells.

Let’s look at an immune response as seen by an immunologist, in this case to a viral infection:

 immune viral

Of note are the wide variety of cell types involved, a requirement for MHC class I and II responses, the presence of antibodies, the potential role of the complement cascade, direct lysis by NK cells, and the potentially complex roles played by macrophages and other myeloid cells.

In the immune checkpoint field we have seen the impact of very specific signals on the ability of the T cell immune response to remain productive. Thus, the protein CTLA4 serves to blunt de novo responses to (in this case) tumor antigens, while the protein PD-1 serves to halt ongoing immune responses by restricting B cell expansion in the secondary lymphoid organs (spleen, lymph nodes and Peyer’s Patches) and by restricting T cell activity at the site of the immune response, thus, in the tumor itself. Approved and late stage drugs in the immune checkpoint space are those that target the CTLA4 and PD-1 pathways, as has been reviewed ad nauseum. Since CTLA4 and PD-1 block T cell-mediated immune responses at different stages it is not surprising that they have additive or synergistic activity when both are targeted. Immune checkpoint combinations have been extensively reviewed as well.

We’ll not review those subjects again today.

If we step back from those approved drugs and look at other pathways, it is helpful to look for hints that we can reset a productive immune response by reengaging the innate and adaptive immune systems, perhaps by targeting the diverse cell types and/or pathways alluded to above.

One source of productive intelligence comes from the immune checkpoint field itself, and its’ never-ending quest to uncover new pathways that control immune responses. Indeed, entire companies are built on the promise of yet to be appreciated signals that modify immunity: Compugen may be the best known of these. It is fair to say however that we remain unclear how best to use the portfolio of checkpoint modulators we already have in hand, so perhaps we can look for hints there to start.

New targets to sift through include the activating TNF receptor (TNFR) family proteins, notably 4-1BB, OX40, and GITR; also CD40, CD27, TNFRSF25, HVEM and others. As discussed in earlier posts this is a tricky field, and antibodies to these receptors have to be made just so, otherwise they will have the capacity to signal aberrantly either because the bind to the wrong epitope, or they mediate inappropriate Fc-receptor engagement (more on FcRs later). At Biogen we showed many years ago that “fiddling” with the properties of anti-TNFR antibodies can profoundly alter their activity, and using simplistic screens of “agonist” activity often led to drug development disaster. Other groups (Immunex, Amgen, Zymogenetics, etc) made very similar findings. Careful work is now being done in the labs of companies who have taken the time to learn such lessons, including Amgen and Roche/Genentech, but also BioNovion in Amsterdam (the step-child of Organon, the company the originally created pembrolizumab), Enumeral in Cambridge US, Pelican Therapeutics, and perhaps Celldex and GITR Inc (I’ve not studied their signaling data). Of note, GITR Inc has been quietly advancing it’s agonist anti-GITR antibody in Phase 1, having recently completed their 8th dose cohort without any signs of toxicity. Of course this won’t mean much unless they see efficacy, but that will come in the expansion cohort and in Phase 2 trials. GITR is a popular target, with a new program out of Wayne Marasco’s lab at the Dana Farber Cancer Institute licensed to Coronado and Tg Therapeutics. There are many more programs remaining in stealth for now.

More worrisome are some of the legacy antibodies that made it into the clinic at pharma companies, as the mechanisms of action of some of these agonist antibodies are perhaps less well understood. But lets for the sake of argument assume that a correctly made anti-TNFR agonist antibody panel is at hand, where would we start, and why? One obvious issue we confront is that the functions of many of these receptors overlap, while the kinetics of their expression may differ. So I’d start by creating a product profile, and work backward from there.

An ideal TNFR target would complement the immune checkpoint inhibitors, an anti-CTLA4 antibody or a PD-1 pathway antagonist, and also broaden the immune response, because, as stated above, the immune system has multiple arms and systems, and we want the most productive response to the tumor that we can generate. While cogent arguments can be made for all of the targets mentioned, at the moment 4-1BB stands as a clear frontrunner for our attention.

4-1BB is an activating receptor for not only T cells but also NK cells, and in this regard the target provides us with an opportunity to recruit NK cells to the immune response. Of note, it has been demonstrated by Ron Levy and Holbrook Khort at Stanford that engagement of activating Fc receptors on NK cells upregulates 4-1BB expression on those cells. This gives us a hint of how to productively combine antibody therapy with anti-4-1BB agonism. Stanford is already conducting such trials. Furthermore we can look to the adjacent field of CAR T therapeutics and find that CAR T constructs containing 4-1BB signaling motifs (that will engage the relevant signaling pathway) confer upon those CAR T cells persistence, longevity and T cell memory – that jewel in the crown of anti-tumor immunity that can promise a cure. 4-1BB-containing CAR T constructs developed at the University of Pennsylvania by Carl June and colleagues are the backbone of the Novartis CAR T platform. It is a stretch to claim that the artificial CAR T construct will predict similar activity for an appropriately engineered anti-4-1BB agonist antibody, but it is suggestive enough to give us some hope that we may see the innate immune system (via NK cells) and an adaptive memory immune response (via activated T cells) both engaged in controlling a tumor. Pfizer and Bristol Myers Squibb have the most advanced anti-4-1BB agonist antibody programs; we’ll see if these are indeed best-in-class therapeutics as other programs advance.

Agonism of OX40, GITR, CD27, TNFRSF25 and HVEM will also activate T cells, and some careful work has been done by Taylor Schreiber at Pelican to rank order the impact of these receptors of CD8+ T cell memory (the kind we want to attack tumors). In these studies TNFRSF25 clearly is critical to support CD8 T cell recall responses, and may provide yet another means of inducing immune memory in the tumor setting. Similar claims have been made for OX40 and CD27. Jedd Wolchok and colleagues recently reviewed the field for Clinical Cancer Research if you wish to read further.

Looking again beyond T cells another very intriguing candidate TNFR is CD40. This activating receptor is expressed on B cells, dendritic cells, macrophages and other cell types involved in immune responses – it’s ligand (CD40L) is normally expressed on activated T cells. Roche/Genentech and Pfizer have clinical stage agonist anti-CD40 programs in their immuno-oncology portfolios. Agonist anti-CD40 antibodies would be expected to activated macrophages and dendritic cells, thus increasing the expression of MHC molecules, costimulatory proteins (e.g. B7-1 and B7-2) and adhesion proteins like VCAM-1 and ICAM-1 that facilitate cell:cell interactions and promote robust immune responses.

I mentioned above that interaction of antibodies with Fc receptors modulates immune cell activity. In the case of anti-CD40 antibodies, Pfizer and Roche have made IgG2 isotype antibodies, meaning they will have only weak interaction with FcRs and will not activate the complement cascade. Thus all of the activity of the antibody should be mediated by it’s binding to CD40. Two other agonist anti-CD40 antibodies in development are weaker agonists, although it is unclear why this is so; much remains to be learned regarding the ideal epitope(s) to target and the best possible FcR engagement on human cells. Robert Vonderheide and Martin Glennie tackled this subject in a nice review in Clinical Cancer Research in 2013 and Ross Stewart from Medimmune did likewise for the Journal of ImmunoTherapy of Cancer, so I won’t go on about it here except to say that it has been hypothesized that crosslinking via FcgRIIb mediates agonist activity (in the mouse). Vonderheide has also shown that anti-CD40 antibodies can synergize with chemotherapy, likely due to the stimulation of macrophages and dendritic cells in the presence of tumor antigens. Synergy with anti-CTLA4 has been demonstrated in preclinical models.

One of the more interesting CD40 agonist antibodies recently developed comes from Alligator Biosciences of Lund, Sweden. This antibody, ADC-1013, is beautifully characterized in their published work and various posters, including selection for picomolar affinity and activity at the low pH characteristic of the tumor microenvironment (see work by Thomas Tötterman, Peter Ellmark and colleagues). In conversation the Alligator scientists have stated that the antibody signals canonically, i.e. through the expected NF-kB signaling cascade. That would be a physiologic signal and a good sign indeed that the antibody was selected appropriately. Not surprisingly, this company is in discussion with biopharma/biotech companies about partnering the program.

Given the impact of various antibody/FcR engagement on the activity of antibodies, it is worth a quick mention that Roghanian et al have just published a paper in Cancer Cell showing that antibodies designed to block the inhibitory FcR, FcgRIIB, enhance the activity of depleting antibodies such as rituximab. Thus we again highlight the importance of this sometimes overlooked feature of antibody activity. Here is their graphical abstract:

 graphical abstract

The idea is that engagement of the inhibitory FcR reduces the effectiveness of the (in this case) depleting antibody.

Ok, moving on.

Not all signaling has to be canonical to be effective, and in the case of CD40 we see this when we again turn to CAR T cells. Just to be clear, T cells do not normally express CD40, and so it is somewhat unusual to see a CAR T construct containing CD3 (that’s normal) but also CD40. We might guess that there is a novel patent strategy at work here by Bellicum, the company that is developing the CAR construct. The stated goal of having a CD40 intracellular domain is precisely to recruit NF-kB, as we just discussed for 4-1BB. Furthermore, the Bellicum CAR T construct contains a signaling domain from MYD88, and signaling molecule downstream of innate immune receptors such as the TLRs that signal via IRAK1 and IRAK4 to trigger downstream signaling via NF-kB and other pathways.

Here is Bellicum’s cartoon:

 cidecar

If we look through Bellicum’s presentations (see their website) we see that they claim increased T cell proliferation, cytokine secretion, persistence, and the development of long-term memory T cells. That’s a long detour around 4-1BB but appears very effective.

The impact of innate immune signaling via typical TLR-triggered cascades brings us to the world of pattern-recognition receptors, and an area of research explored extensively by use of TLR agonists in tumor therapy. Perhaps the most notable recent entrant in this field is the protein STING. This pathway of innate immune response led to adaptive T cell responses in a manner dependent on type I interferons, which are innate immune system cytokines. STING signals through IRF3 and TBK1, not MYD88, so it is a parallel innate response pathway. Much of the work has come out of a multi-lab effort at the University of Chicago and has stimulated great interest in a therapeutic that might be induce T cell priming and also engage innate immunity. STING agonists have been identified by the University of Chicago, Aduro Biotech, Tekmira and others; the Aduro program is already partnered with Novartis. They published very interesting data on a STING agonist formulated as a vaccine in Science Translational Medicine on April 15th (2 weeks ago). Let’s remember however that we spent several decades waiting for TLR agonists to become useful, so integration of these novel pathways may take a bit of time.

This emerging mass of data suggest that the best combinations will not necessarily be those that combine T cell immune checkpoints (anti-CTLA4 + anti-PD-1 + anti-XYZ) but rather those that combine modulators of distinct arms of the immune system. Recent moves by biopharma to secure various mediators of innate immunity (see Innate Pharma’s recent deals) and mediators of the immunosuppressive tumor microenvironment (see the IDO deals and the interest in Halozyme’s enzymatic approach) suggest that biopharma and biotech strategists are thinking along the same lines.

ICI15 presentation is now available

Over 100 slides on immune checkpoint combination therapy, novel targets and drug development in immuno-oncology, created for a 3 hour workshop at ICI15 (link).

As always we work from indications to discovery and back again, keeping one eye on the rapid evolution of clinical practice in oncology and the other on novel targets and therapeutics.

on SlideShare now:

Immune Checkpoint Conference Interview (PDF)

Hit the link to see the full text (PDF) of Paul Rennert’s interview by Fiona Mistri, representing ICI15. The Immune Checkpoint Conference is being held next month in Boston.

Paul Rennert SugarCone Biotech LLC