Category Archives: Genentech

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:


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.

The twisted tale of neoantigens and anti-tumor immune responses

Two papers out this week add to a pile of data addressing the role of neoantigens in tumor therapy. While these papers address tumor neoantigen “load” in the context of immune checkpoint therapy the results have implications for TIL therapeutics, TCR therapeutics and onco-vaccine development.

A really dramatic paper from diverse groups at the University of Pennsylvania and their collaborators, just published in Nature (link-1), explores the complex interplay of radiation therapy and anti-CTLA4 antibody therapy (ipilimumab, from BMS) in patients with stage IV metastatic melanoma (relapsed or previously untreated). In this Phase 1/2 clinical trial (NCT01497808) patients with multiple melanoma metastases received various doses of radiation therapy delivered to a single metastasis, termed the “index lesion”. They then received 4 doses of ipilimumab (3 mg/kg, i.v., once every 3 weeks) and non-irradiated lesions were evaluated within 2 months of the last dose.

Although the sample size reported is small (n=22) some interesting lessons emerged from the study. The response rate was low, and the progression free survival (PFS: 3.8 months) and overall survival (OS: 10.7 months) data bear this out. It appears that just shy of 40% of patients were still alive at ~30 months (see Figure 1c in the paper). It is too early to tell if there will be a “long-tail” effect going forward. In the original ipilimumab study a very small percentage of patients lived for a very long time, “pulling” the PFS and OS curves to the right. Regardless, most patients in this study did not respond and the questions posed in this paper are directed to the mechanisms of resistance.

The mouse B16-F10 melanoma model was used to model resistance. Mice with tumors were locally irradiated then treated with an anti-mouse-CTLA4 antibody, to mimic the clinical trial. Only 17% of the treated mice responded. Two predictors of response/non-response were elucidated: 1) the ratio of effector T cells (Teff) to regulatory T cells (Treg) and 2) a gene signature in the tumor cells that is dominated by the expression of PD-L1 and IFNgamma regulated genes. In short, if the melanoma cells are expressing PD-L1 and the tumor infiltrating lymphocyte (TIL) population is dominated by Tregs (which are PD-1+), then the radiation + anti-CTLA4 therapy failed.

To further subset TIL into active Teff versus non-responsive “exhausted” Teff, the authors used an expression profile of PD-1+/Eomes+ to identify exhausted Teff and PD-1+/Eomes+/Ki67+/GzmB+ for active Teff. Importantly, exhausted Teff could be reanimated upon treatment with PD-1 pathway antagonists: anti-PD-1 antibody or anti-PD-L1 antibody. This reanimation led to an improved CD8+ Teff/Treg ratio and led to tumor control in the majority of the mice (up to 80%) when the treatment consisted of irradiation plus anti-CTLA4 plus anti-PD-L1. Of note, radiation plus anti-PD-L1 did not achieve this effect; the triple therapy was required (see Figure 2d).

The striking conclusion is that upregulation of PD-L1 on tumor cells can subvert the effect of anti-CTLA4 antibody therapy, and this therefore qualifies as a mechanism of resistance.

What about the role of irradiation? In both the patients and the mouse model irradiation was local, not systemic. Further, this local irradiation was required to achieve complete responses in the mouse model. What is going on here? Irradiation was linked to a modest increase in TIL infiltration of melanoma tumors in the mouse model, but sequencing of the T cell receptors (TCR) revealed that there was an increase in the diversity of TCRs, meaning that more antigens were being recognized and responded to by TIL after irradiation. In this context then, anti-CTLA4 reduced the Treg population, anti-PD-L1 allowed CD8+ TIL expansion, and irradiation set the antigenic landscape for response.

Returning to the patients armed with this information from the mouse study, the authors find that low PD-L1 expression on the melanoma cells correlates with productive response to irradiation plus ipilimumab therapy, while PD-L1 high expressing tumors were associated with persistent T cell exhaustion. In addition, monitoring the state of the CD8+ T cell population (PD-1+/Eomes+ versus PD-1+/Eomes+/Ki67+/GzmB+) suggested that these phenotypes might be useful as peripheral blood biomarkers. The patient numbers are very small for this analysis however, which awaits further validation.

The conclusion: irradiation combined with ipilimumab plus anti-PD-L1 antibody therapy should be a productive therapeutic combination in PD-L1+ stage IV melanoma. Similar strategies may be beneficial in other solid tumor types. This is interesting news for companies developing anti-PD-L1 antibodies, including BMS-936559 (also from BMS), MPDL3280A (Roche/Genentech), MEDI4736 (AZN) and MSB0010718C (Merck Serono).

A second paper (link) bring our focus back to PD-1, in the context of non-small cell lung cancer (NSCLC). Using the anti-PD-1 antibody pembrolizumab (from Merck) a group from the Memorial Sloan-Kettering Cancer Center sought to determine correlates of response of NSCLC patients to anti-PD-1 therapy. Their findings again hone in on neoantigen load, as the best predictors of response were the non-synonymous mutational burden of tumors, including neoantigen burden and mutations in DNA repair pathways. What all this means is that mutations that change the amino acid sequence (thus, are non-synonymous) can produce neoantigens that can be recognized by CD8+ T cells; mutations in the DNA repair pathways increase the rate that such mutations go uncorrected by a cell.

The authors sequenced the exomes (expressed exons – these encode proteins) from tumors versus normal tissue, as a measure of non-synonymous mutational burden that could produce neoantigens. Patients were subsetted based on response: those with durable clinical benefit (DCB) and those with no durable benefit (NDB). High mutational burden was correlated with clinical efficacy: DCB patients averaged 302 such mutations, while NDB patients averaged 148; ORR, PFS and OS also tracked with mutational burden. In a validation cohorts the number of non-synonymous mutations was 244 (DCB) versus 125 (NDB).

Examination of the pattern of exome mutations across both cohorts was studied in an attempt to discern a pattern of response to pembrolizumab treatment. The mutational landscape was first refined using an algorithm that predicts neoepitopes that can be expressed in the context of each patients specific class I HLA repertoire – these are the molecules that bring antigens to cell surfaces and present them to T cells for recognition (I’m simplifying this process but that is the gist of it). The algorithm identified more potential neoepitopes in the DCB patient tumors than in the NDB cohort, more impressively, a dominant T cell epitope was identified in an individual patient using a high-throughput HLA multimer screen. At the start of therapy this T cell clone represented 0.005% of peripheral blood T cells, after therapy the population had risen 8-fold, to 0.04% of peripheral blood T cells. Note that most of this clone of T cell would be found in the tumor, not in circulation, so that 8-fold increase is impressive. The T cells were defined as activated CD8+ Teff cells by expression markers: CD45RA-/CCR7-/LAG3-. As in the first paper we discussed, it is useful that these markers of systemic response to immunotherapy treatment are being developed.

There is an interesting biology at work here. It is often noted that high mutational burden is associated with better outcome, for example to chemotherapy in ovarian cancer, and irrespective of therapy across different tumor types (link-2). This suggests that tumor neoepitopes are stimulating an ongoing immune response that is stifled by active immunosuppression, yet is still beneficial. Once unleashed by immune checkpoint blockade, the immune system can rapidly expand it’s efforts.

We recently reviewed the importance of neoantigens in anti-tumor therapy (link-3) although the focus then was on cellular therapeutics rather than on immune checkpoint modifiers such as anti-CTLA4 and anti-PD-1 or PD-L1 antibodies. We can mow add that our ability to track neoantigens and the immune response to neoantigens is opening new avenues for investigating immuno-oncology therapeutics and their efficacy.

The widget TIGIT

Genentech continues to work on TIGIT, so what the heck is this target? Lets have a look, but first, some context.

T cell constraint is a fundamental attribute of tumor-induced immunosuppression. CTLA4 and PD-1 are central regulators of this process, and antibody blockade of these pathways can restore anti-tumor responses. The state of T cell constraint (non-responsiveness) has been termed anergy in reference to CD4+ T cells and exhaustion in reference to CD8+ T cells. Exhausted CD8+ T cells have a recognizable T cell phenotype characterized by the expression of diverse inhibitory pathways and proteins, including PD-1, TIM-3, LAG-3 and TIGIT. Whether such a phenotype is absolutely selective for exhausted CD8s is a matter of debate, but is a good starting point for a discussion of the need for so many regulatory pathways.

Dual gene-deficient (knock-out) mice and the administration of blocking antibody combinations have shown that the inhibitory receptors can function synergistically to reject tumors in mouse models. The hypothesis that individual co-inhibitory receptors contribute distinct functions to collectively limit T cell responses has recently been tested in human cancer clinical trials, yielding the impressive result that co-blockade of CTLA4 and PD-1 has synergistic and beneficial anti-tumor activity. Such benefit comes with a toxicity cost, as pathological autoimmunity is revealed when the “brakes” come off the immune system.

Why does the T cell arm of immune system require so many different control pathways? This is a reasonable question, which can be answered somewhat glibly with the observation that uncontrolled immunity leads to autoimmune disease and/or chronic inflammation. Still, though, why are multiple breaks required? The working hypothesis is that one pathway (CTLA4) regulates T cell activation by CD28 that normally occurs in the spleen, lymph nodes, Peyer’s patches and other “secondary lymphoid organs” (the thymus, bone marrow and fetal liver are the major primary lymphoid organs). A second pathway (PD-1) is generally thought to regulate “peripheral” T cell activation at the sites of pathogen encounter – in this sense “peripheral” means outside of the lymphoid organs themselves, that is, in the tissues and circulation, or, in the case of cancer immunology, within the tumor. So, simplistically, there is one control pathway (CTLA4) in the house and another (PD-1) in the yard. The recent paper (link 1) describing the release of T cell recognition of tumor antigens upon CTLA4 blockade in melanoma suggests either cross-talk between the compartment (i.e. tumor beds have lymphatic or circulatory drainage to secondary lymphoid organs) or that the role of CTLA4 is more complex than we think.

What about the other control pathways? LAG-3 is a competitive regulator of CD4/MHCII antigen recognition activity and was shown to confer Treg function when transfected into naive CD4+ T cells. The expression of LAG-3 on CD8+ T cells (which are critical for anti-tumor activity) suggests a role in the interaction of CD4+ and CD8+ T cells. LAG-3 is also expressed on tumor cells and may mask tumors from immune recognition. LAG3/PD-1 doubly gene-deficient mice can reject poorly immunogenic tumors that wild-type mice cannot reject. However, the doubly deficient knockout mice also develop pathological and aggressive autoimmunity. These results show that these proteins have distinct roles in regulating immune responses.

TIM-3 has several immune regulatory activities, one of which is to suppress T cell recognition of phosphatidylserine, a molecule expressed on dead and dying cells but also on tumor cells. As with LAG-3 the combination of anti-PD-1 and anti-TIM-3 antibodies had enhanced anti-tumor efficacy in mouse tumor models when compared to either antibody alone.

And now we have TIGIT, an Ig superfamily protein and a member of the PVR/nectin family that includes CD226 (DNAM-1), CD96, CD112 (PVRL2), and CD155 (PVR), among others. The biology of this family of proteins is complex and a little intimidating. Genentech has been prosecuting this pathway for several years, and their new paper (link 2) has perhaps shed additional light on the biology and utility of this target.

One mechanism by which TIGIT modulated immune responses is via the interaction of TIGIT on T cells with CD155 expressed on immature or resting dendritic cells, which blocks maturation signals normally delivered by CD226, that is, TIGIT is a competitive inhibitor of the interaction of CD226 with CD155. The authors note that this system resembles the co-stimulatory/co-inhibitory receptor pair of CD28 and CTLA-4, where CTLA4 is a competitive inhibitor of the interaction of CD28 with B7-1/CD80 and B7-2/CD86. The expression pattern of the receptors is also similar: both TIGIT and CTLA-4 are induced upon cell activation, while the expression of CD226 and CD28 is constitutive.

As alluded to above, and noted explicitly by the Genentech team, the molecular and functional relationships between TIGIT and it’s various ligands/co-receptors are poorly characterized. Furthermore, TIGIT’s role in regulating CD8+ T cell responses and the mechanisms underlying such regulation are not known. Of note, antibodies to TIGIT or PD-L1 alone enhanced CD8+ T cell effector function in tumor-draining lymph nodes, but blockade of both receptors was required to allow activation of CD8+ T cells within the tumor microenvironment, as measured by IFNy production. The authors conclude that TIGIT is a critical and regulator of CD8+ T cell anti-tumor activity. The mechanism of action evoked to explain the role of TIGIT in the tumor setting was addressed using FRET and other analyses. The authors show that TIGIT interacts directly with CD226 to prevent homodimerization, a component of the interaction of CD226 with CD155.

There are a few things to consider here. The animal models were run with very high amounts of anti-TIGIT and anti-PD-L1 antibodies on board (10 mg/kg anti-PD-L1 and 25 mg/kg anti-TIGIT) given 3 times a week. That’s nearly a gram of antibody approximately every 2.5 days. While the anti-PD-L1 antibody used has a mutated Fc domain that cannot mediate direct cell killing by ADCC, the anti-TIGIT antibody used is a wild-type IgG2a isotype antibody and almost certainly mediates direct killing of TIGIT+ cells. While the in vitro FRET assays are suggestive of the proposed mechanism of action, what is actually occurring in vivo is less clear. TIGIT expression on NK cells is also worthy of further exploration.

So I have a doubt. Not that the pathway is important, but that we really have a good sense of how it functions, nor how antagonism of the pathway in patients will impact anti-tumor activity and baseline immune responses. Locally, Drs Vijay Kuchroo and Ana Anderson have done wonderful work on TIGIT biology, and no doubt one or more of the Cambridge immunotherapy companies is working on this target and exploring it’s utility in the tumor setting. Given the expression pattern of TIGIT in tumors – i.e. on PD-1+/TIM3+ “exhausted” T cells – it is certainly worth the effort to find out.

How to select patients who should respond to anti-TIGIT co-therapy (or anti-TIM-3 or anti-LAG-3) is a critical question, best left for another day.

stay tuned