PD-1 And PD-L1 Inhibitors Can Be Expanded To Wide Variety Of Cancers

PD-1 And PD-L1 Inhibitors Can Be Expanded To Wide Variety Of Cancers

Caris Life Sciences announced a publication in which the company’s Caris Molecular Intelligence™ system showed the potential of investigating the expression of two immune checkpoint proteins, the programmed cell death protein 1 (PD-1) and the programmed cell death ligand 1 (PD-L1), in a wide variety of solid tumors.

The study was published in Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research.

Caris Molecular Intelligence is the company’s panomic, comprehensive tumor profiling service that demonstrated the usefulness of evaluating the expression of the PD-1 and PD-L1 proteins. The outcomes of this study may result in two potential targets for a new class of drugs against solid tumors, including aggressive subtypes for which there is no targeted treatment regiments.

The study was based around Caris Molecular Intelligence’s multi-technology approach that integrates different proteomic and genomic aspects. Through these techniques, PD-1 positive tumor-infiltrating lymphocytes (TILs) distribution and cancer cell expression of PD-L1 were analyzed in 437 samples of tumors: 380 carcinomas, 33 sarcomas, 24 melanomas. For each type of the tumors, a different presence of PD-1-positive TILs and PD-L1 expression was registered.

“The emergence of the PD-1 inhibitor class of anticancer agents is one of the most significant therapeutic advances in the field since the advent of targeted therapy (…) Our results are especially timely, as they point to inhibition of PD-1 and PD-L1 as a potentially effective strategy in patient populations for whom it has not previously been considered,” lead author Zoran Gatalica, MD, DSc, executive medical director at Caris Life Sciences said in a press release.

PD-1 And PD-L1

PD-1 is an  immunosuppressive protein molecule upregulated on activated T-cells. When PD-1 binds to its ligand, PD-L1, it becomes activated and decreases the cytotoxic potential of T-cells. PD-1 ligand-receptor interactions are responsible for tumor evasion to an effective immune response. FDA-approved anti-PD-1 drugs such as pembrolizumab (Keytruda) and nivolumab to treat advanced or unresectable melanoma are already in the market.

Although the inhibition of PD-1/PD-L1 checkpoints against tumors is triggering good clinical responses, it is not directed to all types of cancer, since responses are highly dependent on the expression levels of these two proteins.

Results And Highlights Of The Study

PD-1-positive TILs were unusual in some cancer types, but common in ” triple-negative breast cancer (TNBC, a subtype of breast cancer that lacks estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein; 70%), bladder cancer (73%), microsatellite instability high (MSI-H) colon cancer (77%), non-small cell lung cancer (NSCLC, 75%), endometrial cancer (86%), and ovarian cancer (93%),” according to the study. Furthermore, an association was found between the expression of PD-1 positive TILs and increased number of mutations in tumor cells.

Dr. Zoran Gatalica and his team observed that PD-1 and PD-L1  expression was higher in TNBC than in non-TNBC, and MSI-H colon cancers had higher PD-1 and PD-L1 expression than microsatellite-stable (MSS) colon cancers. In NSCLC, co-expression of PD-1 and PD-L1 was observed in 8 cases that lacked other genetic alterations.

Sandeep K. Reddy, MD, chief medical officer of Caris Life Sciences, explained: “These latest findings further validate previous studies documenting PD-1 and PD-L1 expression in several common human malignancies, while also yielding new information about expression of these checkpoint proteins in some less common, difficult-to-treat cancers, for which patients tend to have fewer treatment options (…) Given that other researchers have reported long-term, durable responses to PD-1 inhibitors in patients with advanced melanoma, kidney cancer, and NSCLC, our results may help further demonstrate which tumor types should be prioritized for future clinical trial investigations.”