Case Study: Neoantigen TCR Gene Therapy Yields Metastatic Pancreatic Cancer Regression

Adoptive cellular therapy targeting the KRAS G12D hot-spot mutation with cells engineered to express a T-cell receptor (TCR) gene resulted in tumor regression in a 71-year-old patient with metastatic pancreatic adenocarcinoma, according to findings from a case study published in The New England Journal of Medicine.¹

An overall objective partial response of 62% was achieved in the regression of metastatic lung lesions at 1-month follow-up, and an overall partial response of 72% in tumor regression was achieved by the 6-month mark. Additionally, the engineered cells made up 2.4% of all circulating T cells at 6-months post-treatment.

“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” first author Rom Leidner, MD, medical director, Head & Neck Cancer Program, Providence Cancer Center and Earle A Chiles Research Institute, and colleagues wrote in a brief report.²

While TCR gene therapy can target intracellular tumor-specific antigens, the investigators noted that it is dependent on the specific HLA genotype of the patient.² Therefore, the TCR therapy used in this study, which is restricted by HLA-C*08:02, is only applicable for a low percentage of potential patients. HLA-C*08:02 is only expressed in about 11% of black persons and 8% of white persons in the United States and is expressed in even lower percentages in most other racial and ethnic groups.

“However, additional TCRs targeting KRAS G12D and other hot-spot KRAS mutants restricted by different HLA molecules that have been identified could extend TCR gene therapy against mutant KRAS to a larger number of patients,” Leidner and colleagues noted.² “The immunologic targeting of mutant KRAS with vaccines in patients with pancreatic cancer has also been attempted, but the clinical usefulness of this approach remains unclear.”

A post-treatment biopsy to assess the tumor infiltration by the transduced T cells was not possible due to the rapidness of the tumor regression, also limiting the study.

Prior to infusion, the patient received 600 mg intravenous tocilizumab to prevent cytokine release syndrome followed by intravenous cyclophosphamide. The patient then received a single infusion of 16.2×10⁹ autologous T cells that had been genetically engineered to express 2 allogeneic HLA-C*08:02–restricted TCRs targeting mutant KRAS G12D. Post-infusion, the patient received intravenous high-dose interleukin-2 (600,000 IU per kilogram; one dose every 8 hours, 5 doses total) to support cell expansion.

After treatment, the patient experienced nausea and myelosuppression, which the investigators noted have been associated with cyclophosphamide preconditioning therapy. The patient also experienced hypotension during the post-treatment course of filgrastim administration. However, the investigators noted that “no toxic effects of the engineered T-cell therapy were observed.”²

The investigators also mentioned a similar recent case study with less conclusive results, in which a patient with pancreatic cancer was treated under a separate single-patient investigational new drug application, with autologous T cells engineered to express the 2 HLA-C*08:02–restricted KRAS G12D–reactive TCRs. The cells were manufactured under different in vitro growth conditions without additional immune modulation with tocilizumab.

“Radiographic imaging 1 month after the infusion showed modest regression of the patient’s lung metastases and stable liver lesions. However, despite high levels of T-cell persistence in the blood, the patient had progressive disease and died 6 months after receipt of the therapy,” Leidner and colleagues noted.²

The investigators concluded that prospective clinical trials are warranted to determine the therapeutic potential of this therapy in pancreatic cancer and other cancers that express KRAS G12D.

REFERENCES

1. Leidner R, Silva NS, Huang H, et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer (Research Summary). N Engl J Med.Published online June 9, 2022. doi:10.1056/NEJMoa2119662.

2. Leidner R, Silva NS, Huang H, et al. Neoantigen T-cell receptor gene therapy in pancreatic cancer. N Engl J Med. 2022;386:2112-9. doi:10.1056/NEJMoa2119662.