Journal Publication: CHI3L1 regulates PD-L1 and anti–CHI3L1–PD-1 antibody elicits synergistic antitumor responses.

“Master Pathway” Discovery.

Congratulations to our Founder and Scientific Advisory Board Chairman, Dr. Jack A. Elias, on the publication of his breakthrough lung cancer research in the Journal of Clinical Investigation.

Referring to the important role played by CHI3L1 in lung cancer metastasis in the accompanying authors note, Dr. Elias says, “We believe we have discovered a master pathway that regulates immune checkpoint inhibitors in the lung, and in turn controls the ability of tumor cells to spread to the lung and grow once they’re in the lung.”

He notes that, “these are very novel observations that give us a completely new vision for the processes that regulate immune checkpoint inhibition.”

Dr. Elias also notes that based on these findings his team believes they have developed, “…anti-CHI3L1 monoclonal antibodies and bi-specific antibodies that are exciting potential therapeutics…”

In the article’s abstract, Dr. Elias and his team provide a full summary of their research:

“Evasion of the immune response is a hallmark of cancer, and programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) are major mediators of this immunosuppression. Chitinase 3–like 1 (CHI3L1) is induced in many cancers, where it portends a poor prognosis and contributes to tumor metastasis and spread. However, the mechanism(s) that CHI3L1 uses in metastasis have not been defined. Here we demonstrate that CHI3L1 regulates the expression of PD-L1, PD-L2, PD-1, LAG3, and TIM3 and plays a critical role in melanoma progression and lymphatic spread. CHI3L1 also contributed to IFN-γ–stimulated macrophage PD-L1 expression, and RIG-like helicase innate immunity suppressed CHI3L1, PD-L1, and melanoma progression. Individual antibodies against CHI3L1 or PD-1 had discrete antitumor effects and additive antitumor responses in metastasis models and T cell–tumor cell cocultures when administered simultaneously. Synergistic cytotoxic tumor cell death was seen in T cell–tumor cell cocultures, and significantly enhanced antitumor responses were seen in in vivo tumor models treated with bispecific antibodies that simultaneously target CHI3L1 and PD-1. CHI3L1 contributes to tumor progression by stimulating the PD-1/PD-L1 axis and other checkpoint molecules. The simultaneous targeting of CHI3L1 and the PD-1/PD-L1 axis with individual and, more powerfully, with bispecific antibodies represents a promising therapy for pulmonary metastasis and progression.”

We are looking forward to helping Dr. Elias and his team take the next steps in the development process for these important discoveries.