A case study of a patient with refractory, progressive pancreatic cancer who benefited from a single infusion of a novel T-cell receptor (TCR) transduction therapy holds promise ― but only for the small subgroup of patients with the same KRAS G12D mutation and the right allele.
“Pancreatic ductal adenocarcinoma is resistant to current immunotherapies and remains one of the most lethal cancers in humans,” Rom Leidner, MD, Earle Chilies Research Institute, Providence Cancer Institute, Portland, Oregon, and colleagues point out.
“In this patient, TCR gene therapy targeting the KRAS G12D driver mutation mediated the objective regression of metastatic pancreatic cancer…. Tumor regression was ongoing at the latest follow-up, 6 months after the cell transfer,” the investigators report.
The study was published online June 1 The New England Journal of Medicine.
Initially, the Patient Was Heavily Pretreated
Prior to receiving the novel therapy, the 67-year-old female patient had been heavily pretreated. She had received neoadjuvant chemotherapy (FOLFIRINOX), then surgery, then adjuvant treatment with FOLFIRINOX again, as well as additional adjuvant chemoradiotherapy and concurrent capecitabine. She had also previously been treated with autologous tumor-infiltrating lymphocyte therapy plus high-dose interleukin-2, neither of which halted the progression of lung metastases.
The patient received the novel therapy in June 2021 after first undergoing a preconditioning regimen with the anti-interleukin-6 agent tocilizumab (Actemra) to prevent cytokine release syndrome. She also received cyclophosphamide.
The autologous T cells used in the infusion had been engineered to express allogeneic TCRs, targeting neoantigen KRAS G12D expressed by the tumor, the authors note.
Some 18 hours after receiving the cell infusion, the patient received high-dose interleukin-2 (600,000 IU/mL intravenously every 8 hours for a total of five doses).
A partial response of 72% was maintained 6 months after the infusion, at which point the transduced T cells constituted 2.4% of all T cells in the patient’s circulation. Most of these were CD8+ cells.
The patient was discharged from the hospital on day 11. She received blood product support and myeloid growth factor. The absolute neutrophil count had recovered by day 21 after the cell infusion, and the platelet count had recovered by day 28.
Novel Therapy Used in Second Patient
The investigators have now treated a second pancreatic cancer patient who had the same KRAS mutation and the same HLA allele as the first patient had, using autologous T cells that had again been engineered to express KRAS G12D-reactive TCRs.
This second time, tocilizumab was not part of the preconditioning chemotherapy regimen. After receiving four doses of high-dose interleukin-2, the second patient developed grade 3 cyctokine release syndrome and had a grade 2 immune-effector cell-associated neurotoxic event.
Despite a high level of persistence of TCR-transduced T cells in the patient’s circulation, this time there was no benefit from the infusion of transduced T cells.
Good and Bad News
“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,” Cornelis Melief, MD, PhD, Leiden University Medical Center, Leiden, Belgium, writes in an accompanying editorial.
“The bad news is that patients with the same mutation but without this HLA-allele cannot benefit,” he added. This will limit TCR-transduction therapy to a relatively small proportion of patients. In the US, only about 8% of White patients and about 11% of Black patients carry the necessary allele.
Nevertheless, Melief says the results are “remarkable” because they show “deep” and “durable” tumor shrinkage in a heavily pretreated patient. They suggest that mutation-derived neoantigens such as the KRAS mutation can be targeted efficiently by T cells in a highly specific manner without any toxic effects on healthy cells.
In a separate editorial, Elizabeth Phimister, PhD, deputy editor, and Eric Rubin, MD, PhD, editor-in-chief, The New England Journal of Medicine, explain how targeting cytotoxic T cells to tumors is done. “Because [this] is highly personalized, this approach isn’t easy,” they caution. They explain that for every potential antigen, a TCR must be generated that is specific for both the peptide and the correct HLA class I molecule.
For example, the TCR used in the current study might be used in up to 10% of patients, but many other HLA class I types are not as widely shared — “so this approach would generally require substantial personalization,” they stress. Nevertheless, “if this approach could be used only to treat pancreatic cancer, it would still be exciting,” they emphasize.
“Moreover, almost all tumors are defined by somatic mutations that create unique peptides. In principle, these peptides could all be potential targets for TCRs that could be used for therapy,” Phimister and Rubin conclude.
N Eng J Med. Published online June 1, 2022.
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