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KRAS-Directed TCR Therapy Shows Promising Preclinical Efficacy and Safety

AFNT-111 showed anti-tumor activity in NSG mouse models of breast cancer, pancreatic cancer, and colon cancer.

Affini-T Therapeutics’ AFNT-111, an investigational T-cell receptor (TCR)-engineered therapy that targets KRAS G12V-expressing tumor cells with the intention of treating patients with solid tumors, has demonstrated promising potency and specificity in preclinical studies.

The data were presented at the Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting, November 8-12, 2022, in Boston, Massachusetts, by Hubert Lam, PhD, vice president of Preclinical Development, Affini-T Therapeutics.

AFNT-111 is comprised of autologous CD4+ and CD8+ T-cells that have been transduced to express both a TCR with high affinity for KRAS G12V mutations, which account for approximately 30% of KRAS mutations, and a CD8α/β co-receptor which allows for MHC 1 target recognition and induces a CD4+/CD8+ T-cell response which helps to prevent exhaustion and enable T-cell persistence. AFNT-111 utilizes a TCR candidate that has been identified from healthy donor TCRs with a discovery platform developed in collaboration with Fred Hutch Cancer Research Center. The TCRs identified by the platform are high-affinity and have cleared thymic selection for self-reactivity. The AFNT-111 TCR was additionally verified to be able to recognize endogenous KRAS G12V presented by cell lines derived from various cancer types including pancreatic, colon, lung, breast, and ovarian.

“At Affinity Therapeutics we believe that a key vulnerability of cancer are these oncogenic driver mutations,” Lam said during his presentation. “Since they're responsible for the cancer itself, they're truncal, ubiquitously expressed throughout the tumor. So, if you can kill the cancer cells that have them, you can limit tumor escape and address the whole tumor. In addition, since these are mutated proteins unique to cancer they can be recognized as foreign by the immune system, limiting the safety concerns associated with targeting non-mutated self-antigens. KRAS is the most frequent of these oncogenic drivers in solid tumors, present in an enormous number of human cancers including pancreatic, colorectal, and lung.”

In vitro data showed that AFNT-111 cells had increased ability to control and kill recognized tumor cells compared to untransduced (UTD) controls in several of these cell lines. This ability remained in the face of rechallenges with additional tumor cells, indicating AFNT-111 cells’ potential for persistence. Increased anti-tumor activity of AFNT-111 compared to UTD controls was also seen in immunodeficient NOD scid gamma (NSG) mouse models of breast cancer, pancreatic cancer, and colon cancer. In terms of safety, an in-silico assessment across the human proteome based on XScan assay results indicated 22 peptides of potential concern. However, of these, the study did not identify any cross-reactive self-peptides of concern.

“These 22 peptides were tested with no cross-reactivity identified,” Lam explained during his presentation. “RAB7B was a peptide that had weak potential cross-reactivity; this was further tested, and it had a 400,000-fold lower EC50 as compared to G12V, showing non-biological-relevance at an EC50 of 35 micromolar. We also tested alloreactive responses with no alloreactivity identified in a large B-LCL library, with also no cytokine-independent growth seen with this cell therapy.”

Affini-T Therapeutics is planning to submit an investigational new drug application for AFNT-111 in the first half of next year. The company plans to carry out a phase 1 clinical trial for the therapy along with Fred Hutch Cancer Research Center. The trial will evaluate safety, tolerability, and preliminary efficacy, and aim to determine the maximum tolerated dose. It will include patients with advanced or metastatic pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, or non-small cell lung cancer who are KRAS G12V+ and HLA-A*11:01+.

REFERENCE
Hubert L. AFNT-111, a safe and effective TCR-engineered T cell therapy targeting the oncogenic driver KRAS G12V mutation. Presented at: Society for Immunotherapy of Cancer’s (SITC) 37th Annual Meeting November 8-12, 2022; Boston, Massachusetts. Abstract #244