RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:ONCY pelareorep demonstrates 69% ORR in pancreatic cancer ONCY reported on TCR sequencing in the recent GOBLET Phase 1/2 clinical trial in metastatic pancreatic cancer.
TCR sequencing is a technique that measures the diversity and clonality of T cell receptors (TCRs) in a sample. TCRs are molecules on the surface of T cells that recognize and bind to antigens, which are foreign substances that trigger an immune response. TCR sequencing can provide information about the immune status and activity of a patient, especially in the context of cancer immunotherapy .
Put another way -- TCR sequencing can provide information about the immune status and activity of a patient, especially in the context of cancer immunotherapy, and therefore is considered a predictive biomarker of positive treatment outcome.
TCR sequencing can therefore serve as a surrogate endpoint for clinical trials of cancer immunotherapies, such as checkpoint inhibitors or CAR-T cells. A surrogate endpoint is a measure of effect that can be used instead of a direct measure of clinical benefit, such as survival or quality of life. Surrogate endpoints can help accelerate the development and approval of new therapies, especially for serious or life-threatening conditions .
The rationale for using TCR sequencing as a surrogate endpoint is based on the eidence that TCR diversity and clonality are correlated with the anti-tumor immune response and the clinical outcome of patients. Studies show that higher TCR diversity or clonality in tumor samples or peripheral blood samples are associated with better response rates or survival outcomes in patients treated with immunotherapies .
The validity and reliability of TCR sequencing as a surrogate endpoint is being proven out with pelareorep in the treatment of multiple cancers.
Pelareorep is an oncolytic virus that selectively infects and kills cancer cells while sparing normal cells. Pelareorep also promotes an inflamed tumor phenotype through innate and adaptive immune responses 1. Preliminary clinical trials indicate that it may have anti-cancer effects across a variety of cancer types (including breast, colorectal and pancreatic, as well as multiple myeloma) when administered alone and in combination with other cancer therapies 123.
A recent study published in Frontiers in Oncology explored the possibility of using oncolytic reovirus to sensitize microsatellite stable colorectal cancer to immune checkpoint inhibition 1. The study found that reovirus plus anti-PD-1 treatment increased cell death among microsatellite stable cells ex vivo. Reduced tumorigenicity and proliferative index, and increased apoptosis were evident among CT26 [MSS, KRASMut ], but not in MC38 [microsatellite unstable/MSI, KRASWt] syngeneic mouse models under combinatorial treatment. PD-L1-PD-1 signaling axis were differentially altered among CT26/MC38 models. Combinatorial treatment activated the innate immune system, pattern recognition receptors, and antigen presentation markers. Furthermore, the study observed the reduction of immunosuppressive macrophages and expansion of effector T cell subsets, as well as reduction in T cell exhaustion .
Another study [ Mahalingam D et.al. 2019 ] published in Clinical Cancer Research investigated the combination of pelareorep with pembrolizumab (an immune checkpoint inhibitor) and chemotherapy (emcitaine) for pancreatic ductal adenocarcinoma (PDAC) . The study found that the combination therapy was safe and well-tolerated, with no dose-limiting toxicities observed. The overall response rate was 37.5%, with a disease control rate of 87.5%. The median progression-free survival was 6.2 months, and the median overall survival was 10.8 months, with a 1 and 2 year survival rate of 45% and 24% respectively. The historical 1 year survival rate for mPDAC patients is 10%. The study also found that the combination therapy induced a T-cell–inflamed phenotype in PDAC tumors, as evidenced by increased T-cell infiltration and upregulation of PD-L1 expression .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942612/