Passle Menu 1 TCR T-cell Therapies: What if Magic Bullets Simply Aren't Good Enough? Joel Sandler November 19, 2021 56 On the heels of a recent post in which I discussed evolving dynamics and strategic implications underscoring different types of allogeneic cell therapies in oncology, I find it fitting to address another substantive consideration in the field, that of targeting moieties. Specifically, what can we say about the likely roles to be played by CAR- vs. TCR-modified cell therapies? T-cells have evolved to recognize, engage, and destroy non-self tissue based on binding of T-cell receptors (TCRs) to foreign antigens presented as peptides in complex with MHC (major histocompatibility complex) molecules. Biologically-speaking, there is a lot more going on here. But let’s simply say that TCRs are a natural and arguably necessary component of robust and sustained T-cell responses. In contrast to TCRs, chimeric antigen receptors (CARs) are not a naturally-expressed component of the T-cell. While antibodies (the “R” in CARs) are indeed natural, their conjugation to chimeric intracellular activation domain is not. Whereas CAR-modified T-cells have proven effective in heme malignancies (e.g., B-cell lymphomas, multiple myeloma) that are responsive to transplant-like ablation and add-back of new-and-improved immune compartments, they may be less adept at addressing more heterogenous and microenvironment-bound malignancies. Indeed (and it is sadly as true today as it was when I wrote about it almost 2 years ago), there’s a whole universe of additional oncology indications waiting to be addressed by CAR-T therapies. Many of us first came to learn about the promise of TCR-based therapies with the launch of Immunocore and Adaptimmune in 2008, both of which were co-founded by James Noble with the licensing of TCR technology from Medigene. While the importance of natural T-cell signaling following TCR-mediated tumor recognition has of late become increasingly pertinent to the comparison of TCRs vs. CARs, the fundamental role of TCR signaling in T-cell activity was never the most salient feature of its value proposition as a therapeutic modality. Instead, innovators and investors latched onto the importance of TCRs being able to recognize tumor antigens expressed both outside and within the cell. The correspondingly larger universe of candidate antigens from which to select with TCR-Ts vs. CARs, which can only recognize extracellular antigens (representing ~15% of proteins in the cell), should translate into an increased likelihood of finding clean, ‘magic bullet’ targets needed to achieve robust on- vs. off-tumor targeting. That said, TCRs can only recognize antigens in the context of presentation by HLA (the human version of MHC), which itself exists in flavors that vary across different ethnicities. HLA A2, which is one of the most common HLA subtypes globally, can only be found in ~50% of the U.S. Caucasian population. Candidate patient populations for TCR-Ts are therefore restricted not only by expression rates of the tumor antigens they target but also that of HLA subtype. A therapeutic target expressed in 50% of cancer patients would therefore only be applicable for 25% (0.5 * 0.5) of white patients, and far fewer across other regional markets. Do TCR-based approaches work in solid tumors? Cell therapies are, after all, expensive to develop and manufacture, and they are therefore held to a higher standard in the clinic vs. comparatively simpler biologics and small molecules. And with the vast majority of cell therapy revenues projected for hematological malignancies, market penetration into solid tumors, which comprise the vast majority of cancer patients, is mission critical for cell therapies to succeed. As it turns out, TCR-based therapies have achieved rather impressive clinical performance in certain solid tumor settings. Both Adaptimmune’s afami-cel and GSK’s lete-cel have demonstrated high rates of durable remissions in sarcoma, with hints of activity in broader tumor types like ovarian and gastric cancers. And if we expand our notion of TCR-based approaches to include not only engineered TCR-Ts but also TILs (e.g., Iovance) and virus-targeted T-cells (e.g., Atara), both of which rely upon TCR-mediated recognition and antitumor activity, TCR-based approaches as a group are quite effective across solid tumors. By comparison, CAR-modified cells have languished outside of B-cell malignancies and multiple myeloma. While it remains early days for data readout, CAR-modified cells targeting more prominent (i.e., de-risked) extracellular solid tumor-associated antigens such as HER2, mesothelin, and PSMA have achieved transient responses at best and life-threatening toxicities in more dire cases. So how do we explain the disconnect between allocation of funds and clinical performance of TCR- vs. CAR-based therapies? CAR-T therapies continue to dominate the competitive landscape, comprising ~50% of all cell therapy trials active in 2021 (TCR-Ts account for ~5%). We know TCR-based approaches work in solid tumors. As noted above, Adaptimmune, GSK, Iovance, and Atara have all demonstrated compelling efficacy in solid tumors. In fact, we have known for decades that TIL-based approaches work in solid tumors. That investor and partnering flood-gates have not been thrown open to TCR-based approaches reflects fundamental remaining questions as to whether there is a viable commercial case for these programs: Is the efficacy sufficient to justify premium pricing? Will companies achieve a suitable return if the products only work in rare subgroups? Is the manufacturing scalable if approaches rely on patient-derived (autologous) cells? Can individual products be positioned across multiple tumor types? Are discovery engines capable of repeatedly identifying actionable targets and correspondingly-effective product candidates? TCR-based companies are clearly responding to these market demands that go beyond “merely” achieving efficacy in solid tumors. Companies developing hyper-personalized TCR discovery engines have captured the attention of Pharma (e.g., see deals from TScan/Novartis, Adaptive/Roche). Another approach, that of hybrid CAR-TCRs (TCR2, Triumvira, Eureka), is purportedly capable of expanding upon market potential via MHC-independent antigen recognition while retaining natural TCR-like signaling. Perhaps more to the point, companies developing established TCR-T technology are emphasizing the need to develop multiple clinical programs in parallel, many of which may be effective each across multiple tumor types. Indeed, pipelines of immatics and Anocca are comprised of multiple programs involving similar products that differ only with the antigens recognized by their TCRs. Another means to wresting value from TCR-T therapies is that of building upon existing product candidates with incorporation of additional enabling modifications, as exemplified by GSK and Adaptimmune. Notably, both of these companies are also doubling down on their product candidates by expanding reach across multiple tumor types (e.g., GSK’s efforts to go beyond sarcoma into NSCLC, Adaptimmune’s efforts to expand beyond sarcoma into ovarian cancer). CAR-based companies are not, of course, standing still or willing to accept CD19 and BCMA as the beginning and end of their story. The diversity of variations on the CAR-based theme is simply staggering, and we are finally seeing a slow-down in the number of new programs against these validated but overcrowded targets. That said, T-cell biology is nuanced, and a modification to something so fundamental as antigen-recognition and downstream activation pushes it away from evolution-honed activity. Such a strategy must somehow be compensated for if CAR-based products are to achieve potent, safe, and durable remissions in the clinic. The corollary to this is that we must develop capabilities of understanding how immunity works within the human host. Yes, many modifications are being piloted. And yes, some of them may work. On the other hand, there may not be sufficient funds, even in this space where funds have been plentiful, to support trialing of enough approaches before any emerge with clinical performance sufficient to justify their costs. Unless such costs can be brought down, that is. But that’s a topic for another post. { Do TCR-based approaches work in solid tumors? Cell therapies are, after all, expensive to develop and manufacture, and they are therefore held to a higher standard in the clinic vs. comparatively simpler biologics and small molecules. And with the vast majority of cell therapy revenues projected for hematological malignancies, market penetration into solid tumors, which comprise the vast majority of cancer patients, is mission critical for cell therapies to succeed. 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