T-cell receptor gene therapy induces response in metastatic pancreatic cancer
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A woman with metastatic pancreatic cancer attained a 72% partial response with T-cell receptor gene therapy, according to a report published in The New England Journal of Medicine.
The finding, reported by Rom Leidner, MD, of Providence Cancer Institute, and colleagues, may have future implications for treatment of pancreatic cancer.
“This treatment is completely dependent on identifying the tumor-specific mutation,” Eric J. Rubin, MD, PhD, editor-in-chief of The New England Journal of Medicine, said during a live webinar on the report. “The mutation that caused this tumor is very common, however, so it might be possible to extend this to most other [patients with pancreatic cancer].”
The journal offered the webinar as part of an experimental approach to assist journalists in the reporting of complicated, novel methodologies, Rubin said.
“This was a complicated trial with a complicated methodology,” Rubin said. “We wanted to help reporters tell their stories and be able to help explain the trial’s implications.”
In the presentation, Rubin discussed the 71-year-old patient, who had been diagnosed with adenocarcinoma of the pancreas in 2018 at age 67 years. She underwent FOLFIRINOX chemotherapy, tumor resection and adjuvant chemotherapy, and remained disease-free until 2019, when a fine-needle biopsy revealed lung metastases. The woman then received autologous tumor-infiltrating lymphocyte therapy plus high-dose interleukin-2 therapy. These treatments did not stop progression of the lung metastases.
In June 2021, the woman received a single infusion of T-cell receptor-transduced T cells aimed at mutant KRAS G12D expressed by the cancer cells. One month after this infusion, the metastatic lesions showed partial regression according to RECIST version 1.1. At 6 months, the patient maintained a partial response of 72%.
“The patient who seemed to respond had an unusual treatment history with extensive types of immunotherapies,” Rubin said.
A second patient with the same KRAS mutation and the same human leukocyte antigen allele did not benefit from a similar regimen. This could not be explained by common resistance mechanisms to immunotherapy.
Rubin said although these findings may be intriguing, much more research will be needed to fully understand the potential of this type of regimen.
“Two big caveats — the T-cell receptor has to be specifically matched to an individual patient, and, of course, we have only seen what happened in two patients,” he said. “So, there would need to be a lot more clinical experience.”
In a related editorial, Cornelis J.M. Melief, MD, PhD, of Leiden University Medical Center and ISA Pharmaceuticals, both in the Netherlands, wrote that the results offer hope for a limited number of patients with pancreatic cancer.
“The good news is that all patients who have this particular HLA allele and have tumors that express the KRAS G12D mutation can potentially benefit from this TCR transduction therapy, particularly when some immunotherapy resistance mechanisms are addressed by the appropriate combination therapy,” Melief said. “The bad news is that patients with the same mutation but without this HLA-C allele cannot benefit.”
References:
Leidner R, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2119662.
Melief CJM, et al. N Engl J Med. 2022;doi:10.1056/NEJMe2204283.
Perspective
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Igor Astsaturov, MD, PhD
What is remarkable about this case is the patient mounted a partial response that was sustained for 6 months and correlated with the persistence of engineered T cells. This is the inspirational fact which, I am sure, will boost the morale in the field of cancer immunotherapy and will lead to increased efforts and funding to develop innovative immune-based treatments for pancreatic cancer.
The challenges that lie ahead include reversal of immune suppression in the tumor tissue and making the T-cell immune attack sustainable over time.
Fox Chase Cancer Center
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