“Act 2” for Checkpoint Blockade Therapies in Cancer: Defeating Primary Resistance
November 2nd, 2018 | Nagesh K. Mahanthappa, PhD, MBA

Without a doubt, recent advances in immunotherapy have transformed the treatment of patients with cancer. Many patients with previously intractable cancers are now stabilized or have even had their cancer rendered undetectable. The astounding results seen with checkpoint blockade therapies (CBTs), particularly anti-PD1/PDL1 antibodies, have now established these medicines as a mainstay in cancer treatment, as evidenced by nearly $15 billion in annual sales(1) and significant expected growth. These results have emboldened the cancer R&D community to expand approaches in cancer immunotherapy that aim to increase the number of patients and types of tumors that can respond to CBT durably and with a minimum of adverse events. The need for these efforts is underscored by the fact that more than half of cancer patients do not respond to current approved CBTs(2), and thus, understanding and addressing primary resistance should certainly be a central focus.

Deeper Biology:  Breaking Barriers to Defeat Primary Resistance

Over the past few years, there has been a deluge of efforts to evaluate CBTs in combination therapy settings in order to overcome tumor resistance. More recently, however, this enthusiasm has been tempered by lackluster clinical results and failures when combining CBTs with agents known to affect the same tumor type or to modulate seemingly relevant components of the immune system. Why such disappointing results? A likely reason is that a clear mechanistic rationale for the given combination is often not rooted in clinically-derived data, and has thus led to uncertain and confounding outcomes in trials intended to enhance approved single-agent therapies.

What has become clear from both initial successes and failures in immuno-oncology is that designing combination immunotherapy should be based on scientific evidence of relevance to underlying tumor cell and immune system biology. Rational combination strategies are now emerging from retrospective analyses of the cellular, molecular, and genetic profiling of clinically-derived tumors – both those that are susceptible to CBT and those that are resistant. This approach is shedding new light on key mechanisms, the targeting of which may be more likely to expand the efficacy of current CBTs because they will focus on addressing the actual underlying reasons for a lack of monotherapy response.

Uncovering Immune Exclusion

Some recent and profound observations suggest that generating and preventing the exhaustion of tumor-specific CD8+ T cells is not likely to be enough to mount a successful attack on certain tumors.(3)  In the case of many patients’ tumors, it is the prevention of T cell entry into the tumor that renders CBT ineffective. In these “immune excluded” tumors, anti-tumor T cells are present in patients and accumulate at the tumor site, but fail to efficiently infiltrate and expand into the cellular microenvironment to attack the tumor. The evidence is now clear that mechanisms that affect T cell entry and expansion appear to be a critical part of the cancer immunity cycle that clinically influences response to CBT. Identification of mechanisms to overcome this immune exclusion has the potential to improve the efficacy of existing cancer immunotherapies in a broad range of patients.

Selective Inhibition of TGFβ1 Could be Key in Unlocking Immune Exclusion

Excitingly for Scholar Rock, multiple academic and industrial groups have recently described the link between transforming growth factor beta (TGFβ) and immune exclusion in human tumors. Just this year, Genentech published a paper on the association among i) increased TGFβ signaling, ii) lack of tumor response to anti-PDL1 antibody therapy, and iii) reduced survival based on examinations of tumor samples from patients with metastatic urothelial cancer. (3) In retrospect, this may not be surprising given the well-established role of TGFβ1 as an immunomodulatory growth factor that influences the activity of effector T cells. Importantly, this team also demonstrated in a preclinical model that inhibiting TGFβ can improve therapeutic outcomes when paired with a checkpoint therapy, making it an intriguing combination for clinical development.

Nonetheless, inhibiting TGFβ is not without its own challenges. Development of small molecules, which can broadly inhibit the signaling of all TGF-β isoforms, has long been impeded by on-target toxicities, most notably cardiac injury. An isoform-selective approach could lead to a more favorable safety profile and therefore be better suited to combination therapy. At Scholar Rock, we are developing monoclonal antibodies with high selectivity for TGFβ1 that we are evaluating in preclinical models of oncology, immuno-oncology and fibrosis.

Analyses of Human Tumors Opens New Insights

It is exciting to see new therapeutic hypotheses emerge from retrospective analyses of human tumors and therapeutic response data. The molecular correlations derived from assessing actual human disease responses to CBT should offer a higher probability of finding new entry points that will enhance or overcome inadequate therapeutic effects of what have been transformative medicines for a minority of patients. It is now clear that the cancer immunotherapy drug discovery and development community should move these hypotheses back into preclinical models that better reflect the actual biological mechanisms at play in human tumors. This concept has yet to be put into common practice, as surprisingly little is known about the molecular and immunologic features of the most commonly used preclinical tumor models, which in turn, leads to challenges in pairing an experimental hypothesis with the appropriate model.

Scholar Rock has taken a pragmatic approach to understanding and evaluating different preclinical models by selecting syngeneic mouse tumor models that appropriately reflect human tumor biology. We are excited to share the results from our studies using syngeneic mouse models at the upcoming SITC annual meeting, and we look forward to presenting preclinical data that highlight the role of TGFβ1 inhibition in overcoming primary resistance to CBTs.

The momentum and enthusiasm with which the community of researchers, drug discoverers, clinicians, and patients are working together to strengthen the foothold created by checkpoint blockade therapies is astonishing. The shift towards human evidence-based rational approaches to developing combination immunotherapy is now well under way!

 

(1) Company reports from Bristol Myers Squibb, Merck & Co., and F. Hoffman-La Roche Ltd.

(2) Sharma P, Hu-Lieskovan S, et al. Primary, adaptive, and acquired resistance to cancer Immunotherapy. Cell 2017 Feb 9, 168(4); 707-723.

(3) Mariathasan S, Turley S, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544-548 (2018).

 

NOTE:  Scholar Rock will be presenting results from its TGFβ1 cancer immunotherapy program at the SITC annual meeting that demonstrate the ability of a highly specific inhibitor of TGFβ1 activation to overcome primary resistance to checkpoint blockade (Poster #550, November 9-11, 2018).

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