Activating T cells to fight cancer

Marengo Therapeutics’ breakthrough discovery in T cell receptor (TCR) activation blazes a new trail for safe treatment and long-term protection against cancer.

Immuno-oncology (IO) has transformed cancer care to significantly benefit patients with both blood and solid-tumor malignancies. Despite recent advances, two-thirds of patients do not achieve durable responses to current therapies, which has been largely attributed to dysfunctional T cells. Marengo’s deep understanding of T cell biology and receptor signaling has led to the discovery of novel multi-specific antibodies that target TCR variable beta (Vβ)-chain variants—powerfully activating the right T cells to fight cancer (Fig. 1).

“There is still a vast unmet need for effective and durable IO therapies that can overcome the dysfunctional T cell responses that develop in most cancer patients during the course of treatment,” said Zhen Su, CEO of Marengo. “Our groundbreaking discovery, which is based on the right activation of the right T cells, builds on the foundations laid by T cell therapeutics such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells and T cell engagers.”

“We have applied a precision IO approach by targeting specific Vβ-chain variants of the TCR, to activate subsets of a patient’s own T cells. As a result, a patient’s T cells are able to respond quickly, safely and effectively against solid tumors and enable long-term protection.”

Activation of Vβ T cell subsets primes stimulation of clonally diverse populations of both CD4+ and CD8+ T cells directly through the TCR, turbocharging them to drive anti-tumor responses and long-term immunity.

To date, few T cell-activating antibodies have demonstrated functional memory and long-term protection as a single agent in a broad range of IO-sensitive and resistant solid tumor preclinical models. They have also been limited due to safety concerns. “A patient’s own T cells are powerful—and even more so if activated in the right way,” said Su. “Our approach mimics the natural, non-antigenic mechanism of TCR activation, much akin to bacterial superantigen-induced TCR activation.”

Activation via TCR Vβ solves the current IO challenges of unleashing the right T cell quantity and quality. Furthermore, the technology allows for targeting of different Vβ variants for different therapeutic needs based on baseline Vβ frequencies and prevalence in tumor-infiltrating lymphocytes (TILs).

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