Nicholas Restifo: When Nature is not enough

Nicholas Restifo, Co-founder and Chief Scientist at Marble Therapeutics, shared on Linkedin:

“When Nature is not enough. Recent advances using T cells to treat cancer have already saved many patients lives and advanced our understanding of the basic biology of T cells. Efforts to improve the effectiveness of living cells as drugs has led to a deeper understanding of natural biology and all its complexity, but we can also see the limitations in the natural biology of T cells.

Cellular immunotherapies are comprised of living cells that experience maturation, followed by loss of function and cell death. These simple biological facts has led experimental cellular immunologist to try to create T cells with longer lifespans and enhanced antitumor capabilities.

Conventional T cell therapies face the challenge of balancing cell longevity with potency. The evolutionarily favorable qualities of T cells can limit their persistence due to senescence and exhaustion to prevent autoimmune diseases. However, synthetic T cells can overcome these limitations, potentially revolutionizing cancer treatment. Decades of work have enabled researchers to elucidate the qualities of therapeutic T cells that lead to better patient outcomes. These qualities include T cells capable of robust proliferation, persistence, polyfunctionality, and metabolic fitness.

It’s also becoming clear that for the treatment of solid tumor masses, most (~90%) are which are of epithelial origin, are highly heterogeneous and usually require a polyclonal T cell attack to achieve complete tumor eradication. Loss of function in T cells due to aging, exhaustion, and senescence is accelerated by the tumor bearing state, leading investigators toward efforts to overcome intrinsic limitations in T cells. Powerful new gene knock in and knockout methods, and editing tools, including CRISPR, and its offshoots base editing and prime editing, have made it possible to go beyond natural T cell states to create synthetic T cells, not found in nature.

In our Insight piece which can be found in today’s issue of Journal of experimental medicine, we discuss one particular effort at creating synthetic T cells that involves simultaneous knockout of two genes, BCOR and ZC3H12A, to create a synthetic T cells state that may have qualities of T cell stemness and cytotoxicity. Many thanks to co-author Luca Gattinoni and support from Denitsa Milanova, and colleagues at Marble Therapeutics for working tirelessly to realize this dream.

The future of synthetic T cells may see them endowed with supraphysiological properties, with control systems to regulate their activation and deactivation, a significant departure from natural T cell development. This new frontier of synthetic T-cell states, while promising, also carries risks such as autoimmunity and uncontrolled cell growth, which require careful consideration as this technology advances towards clinical applications.”

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Source: Nicholas Restifo/Linkedin

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