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A novel T-cell receptor (TCR) gene therapy may be effective in treating patients with pancreatic cancer and other cancers that express the KRAS G12D mutation, researchers have found.

Their case study -- published in the (NEJM) -- showed that a heavily pretreated patient with pancreatic ductal adenocarcinoma achieved a deep and durable response when treated with an infusion of autologous T cells transduced with two TCRs directed against mutant KRAS G12D expression, reported Rom Leidner, MD, of Providence Cancer Center in Portland, Oregon, and colleagues.

Specifically, regression of the patient's metastatic lung lesions were observed 1 month after cell infusion, with an overall objective partial response of 62% (based on RECIST version 1.1). That response was ongoing at 6 months, with an overall partial response of 72%.

In an , Cornelis J.M. Melief, MD, PhD, of Leiden University Medical Center in The Netherlands, noted that pancreatic ductal adenocarcinoma is the deadliest of all common cancers for a variety of reasons, including the advanced cancer stage at the time symptoms become apparent, the occult presence of micrometastases in the liver and elsewhere at the time of surgery, and its resistance to chemotherapy and immunotherapy.

Thus, the results reported in the study "are remarkable because it shows deep and durable tumor shrinkage in a heavily pretreated patient," Melief wrote.

As explained by the study authors, G12D is a common KRAS mutation in pancreatic ductal adenocarcinoma as well as other cancers, including non-small cell lung and colorectal cancers.

The results -- though "certainly far from a cure" -- are encouraging, said Eric J. Rubin, MD, PhD, editor-in-chief of the NEJM, during a virtual presentation discussing the science behind the study. "For the first time, we have an approach that could allow the treatment of a large variety of tumors, beyond the small number of tumors that CAR T-cells can be used in."

Rubin, noting that the mutated gene studied here is common in lung and colorectal cancers, said the study could be a "big step towards applying this more commonly in other diseases that are relatively recalcitrant to therapy."

In a previous study, the researchers had identified HLA-C*08:02-restricted TCRs targeting KRAS G12D in the tumor-infiltrating lymphocytes of a patient with metastatic colorectal cancer.

"Treatment of this patient with her autologous KRAS G12D–reactive tumor infiltrating lymphocytes led to the objective regression of visceral metastases, which suggested that the KRAS G12D–reactive TCRs derived from these tumor infiltrating lymphocytes may be used in TCR gene therapy to treat other patients whose tumors express HLA-C*08:02 and KRAS G12D," explained Leidner and colleagues.

As pancreatic cancers frequently harbor KRAS hot-spot mutations, the author's objective was to test the efficacy of TCR gene therapy against mutant KRAS expression by treating two metastatic pancreatic cancer patients with autologous T cells that had been engineered to clonally express two allogeneic HLA-C*08:02–restricted KRAS G12D–reactive TCRs.

The patient who responded to the TCR gene therapy had been treated in 2018 with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) followed by surgery. She subsequently received adjuvant treatment with the same chemotherapy, and additional adjuvant chemoradiotherapy.

She was disease-free until 2019, when a biopsy confirmed the presence of lung metastases, which led to autologous tumor-infiltrating lymphocyte therapy plus high-dose interleukin-2 therapy in 2020. However, her lung metastases continued to progress.

A single-patient investigational new drug application was approved by the FDA in May 2021, and the patient was treated in June 2021 with autologous peripheral-blood T cells that had been retrovirally transduced in two separate batches to express two allogeneic HLA-C*08:02–restricted TCRs targeting mutant KRAS G12D.

While this patient responded to the treatment, the second pancreatic cancer patient with the same KRAS mutation and HLA allele failed to benefit and died 6 months after receiving therapy, despite high levels of T-cell persistence in the blood. Leidner and colleagues were unable to identify any common mechanism of resistance to immunotherapy, and are continuing to investigate the potential mechanism of failure in this patient.

"Although the durability of the clinical response in our patient remains to be determined, this case report shows that TCR gene therapy targeting the KRAS G12D hot-spot mutation was able to mediate the regression of metastatic pancreatic cancer," they concluded. "Prospective clinical trials are warranted to determine the therapeutic potential of this therapy in pancreatic cancer and other cancers that express KRAS G12D."

"The hard part of this is getting it applied to individual patients because of the restriction of HLA," he said. "How you scale that up, I'm not sure. Right now it is incumbent on the people who are trying to advance this technology to show that it works in anyone -- convincingly -- before tying to figure out how to scale this up and use it for a lot of other different diseases. There is a clear intellectual path for that, but the actual logistics could be complicated."

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