By Michael Fehlings, PhD
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Therapeutics for solid tumors remain in a nascent corner of cancer research despite representing 90 percent of all cancers in adults. Thirty years after the first Chimeric Antigen Receptor (CAR) was reported, CAR-T cell therapies have seen significant breakthroughs managing liquid tumors that can affect the bone marrow, blood cells, and the lymphatic system. Yet, the CAR-T approach, where T cells are engineered against specific targets on the tumor surface to locate and fight cancerous cells more effectively, has had limited impact on solid tumors.
Another approach, T-cell receptor (TCR)-based therapies—where cancer cells are identified and eliminated through highly-specific and sensitive T-cell receptors (TCR)—represents a promising therapeutic alternative. T cell receptor–based therapies harness the unique features of TCRs to recognize a wide range of tumor-specific surface and intracellular targets in different types of cancer. However, TCR-based therapeutics are caught in a discovery bottleneck which limits its applicability. Despite the evolution of cancer target identification, too few TCR targets have been discovered to address the unmet need, and suitable treatment is currently restricted to a minor global patient population.
In recently published peer-reviewed research, ImmunoScape demonstrated that its cutting-edge machine learning platform can accurately predict antigen specificity of human T-cells. By probing hundreds of blood samples for T cell specificity using its unique multiplex high-throughput T cell target screening platform, ImmunoScape has built a massive database of high-quality and functionally validated TCRs against different target classes, which was leveraged for training of its machine learning models. This study shows the capabilities of machine learning and opens possibilities for accelerating the challenging discovery of novel TCRs that could be transformed into TCR-based therapeutics.
Leveraging its Deep Immunomics and machine learning platforms, ImmunoScape has built a discovery engine that offers 360-degree views of lab-validated data from millions of T cells. More than 100 functionally validated TCRs have been identified to date, with many more in the discovery pipeline. With a constantly growing repertoire of high-quality and functionally validated TCR data, ImmunoScape continues to refine its machine learning augmented processes to build an emerging pipeline to enable faster discovery of tumor-specific TCRs against novel tumor targets covering a globally diverse patient population.
ImmunoScape’s diverse TCR portfolio generates opportunities beyond T cell engineering and is applicable to multiple product modalities. TCRs can be used to equip a variety of immune cells with specific tumor-targeting potential, while taking advantage of unique cell characteristics, such as distinct trafficking or enhanced cytotoxicity. For example, TCR-NK (Natural Killer) cell therapies can focus potent cytotoxic NK-cell activity toward tumors bearing targeted antigens. This approach can also be applied to multiple off-the-shelf (allogeneic) cell therapies using cost-efficient manufacturing processes.
Combination therapies, complimented with TCR-engineering, further present opportunities to overcome the known challenges associated with solid tumors, such as suppressive tumor microenvironments, or to enhance overall T-cell fitness for deep and durable anti-tumor responses.
In some cases, TCRs are best deployed as soluble proteins re-directing endogenous T cells, rather than delivered cell therapies. Currently, there is an FDA-approved TCR-based bispecific highlighting the success of this modality. ImmunoScape’s research in building novel affinity-enhanced TCR-based bispecifics for selected tumor targets from its TCR portfolio is on the horizon.
Emerging technological advances across drug development will enable and accelerate delivery of efficacious TCR-based therapies to greater numbers of patients. The prospect of multiplexing TCRs offers a powerful approach to combat HLA and tumor antigen heterogeneity. The integration of TCRs into emerging mRNA-based delivery methods pose additional intriguing possibilities for off-the-shelf manufacturing approaches to bring multi-TCR therapies to patients on a global scale.
The development of TCR-based therapeutics across modalities will not only accelerate the delivery of treatment for solid tumors, but it also holds the potential to cut off cancer before it develops.
Michael Fehlings, PhD, co-founded ImmunoScape, a biotech company focused on the discovery and development of next generation TCR-based therapeutics against solid tumors. He serves as vice president, innovation and established the company’s high-throughput TCR discovery platform.
