KRAS-targeted T-cell therapy derails metastatic cancer

Adoptive transfer of cytotoxic T cells targeting a specific KRAS mutation (KRAS G12D) expressed by a metastatic colorectal cancer induced the regression of all seven lung metastases in a single patient, investigators report in the New England Journal of Medicine.

Mutations of the KRAS oncogene are frequent and drive the formation and progression of many human cancers. “The high incidence of KRAS G12D expression in [colorectal, pancreatic, and multiple other] cancers means that in the United States alone, thousands of patients per year would be potentially eligible for T-cell–based immunotherapy targeting KRAS G12D,” said Eric Tran, PhD, and his associates in the surgery branch, National Cancer Institute, Bethesda, Md.

They described the case of a 50-year-old woman participating in an ongoing phase II clinical trial assessing adoptive transfer of tumor-infiltrating lymphocytes targeting personalized cancer neoepitopes (individualized T-cell therapy). This patient was the only participant to date in whom the treatment induced tumor regression.

A total of 3 of her 10 lung metastases were resected to identify mutations expressed by the tumors, and these were found to express mutant KRAS G12D and HLA-C*08:02. The lymphocyte cultures that reacted most strongly against these antigens were expanded and made into a single infusion, which was administered after the patient had undergone nonmyeloablative conditioning using cyclophosphamide and fludarabine. The patient then received five doses of interleukin-2, which produced the only adverse effect of the entire regimen, fatigue.

At 40-day follow-up, all seven remaining lung metastases showed marked regression. One lesion showed progression at 9-month follow-up and was resected, and the patient has remained cancer free for the subsequent 4 months (N Engl J Med. 2016 Dec 8. doi:10.1056/NEJMoa1609279).

Laboratory analysis of the one metastasis that progressed showed that it had mutated further, losing heterozygosity of the copy of chromosome 6 that encoded HLA-C*08:02. “The presence of this molecule is required for direct tumor recognition by the transferred KRAS G12D-specific T cells. ... [Such a loss] has been observed in human cancers and may represent a hurdle that needs to be overcome to enhance immunotherapeutic efficacy in some patients,” Dr. Tran and his associates wrote.

“In such cases, targeting antigens that are presented by the remaining HLA class I alleles or exploiting the CD4+ T-cell response or the innate immune system against cancer may be necessary to induce a durable clinical response,” they added.

Adoptive transfer of cytotoxic T cells targeting a specific KRAS mutation (KRAS G12D) expressed by a metastatic colorectal cancer induced the regression of all seven lung metastases in a single patient, investigators report in the New England Journal of Medicine.

Mutations of the KRAS oncogene are frequent and drive the formation and progression of many human cancers. “The high incidence of KRAS G12D expression in [colorectal, pancreatic, and multiple other] cancers means that in the United States alone, thousands of patients per year would be potentially eligible for T-cell–based immunotherapy targeting KRAS G12D,” said Eric Tran, PhD, and his associates in the surgery branch, National Cancer Institute, Bethesda, Md.

They described the case of a 50-year-old woman participating in an ongoing phase II clinical trial assessing adoptive transfer of tumor-infiltrating lymphocytes targeting personalized cancer neoepitopes (individualized T-cell therapy). This patient was the only participant to date in whom the treatment induced tumor regression.

A total of 3 of her 10 lung metastases were resected to identify mutations expressed by the tumors, and these were found to express mutant KRAS G12D and HLA-C*08:02. The lymphocyte cultures that reacted most strongly against these antigens were expanded and made into a single infusion, which was administered after the patient had undergone nonmyeloablative conditioning using cyclophosphamide and fludarabine. The patient then received five doses of interleukin-2, which produced the only adverse effect of the entire regimen, fatigue.

At 40-day follow-up, all seven remaining lung metastases showed marked regression. One lesion showed progression at 9-month follow-up and was resected, and the patient has remained cancer free for the subsequent 4 months (N Engl J Med. 2016 Dec 8. doi:10.1056/NEJMoa1609279).

Laboratory analysis of the one metastasis that progressed showed that it had mutated further, losing heterozygosity of the copy of chromosome 6 that encoded HLA-C*08:02. “The presence of this molecule is required for direct tumor recognition by the transferred KRAS G12D-specific T cells. ... [Such a loss] has been observed in human cancers and may represent a hurdle that needs to be overcome to enhance immunotherapeutic efficacy in some patients,” Dr. Tran and his associates wrote.

“In such cases, targeting antigens that are presented by the remaining HLA class I alleles or exploiting the CD4+ T-cell response or the innate immune system against cancer may be necessary to induce a durable clinical response,” they added.

Adoptive transfer of cytotoxic T cells targeting a specific KRAS mutation (KRAS G12D) expressed by a metastatic colorectal cancer induced the regression of all seven lung metastases in a single patient, investigators report in the New England Journal of Medicine.

Mutations of the KRAS oncogene are frequent and drive the formation and progression of many human cancers. “The high incidence of KRAS G12D expression in [colorectal, pancreatic, and multiple other] cancers means that in the United States alone, thousands of patients per year would be potentially eligible for T-cell–based immunotherapy targeting KRAS G12D,” said Eric Tran, PhD, and his associates in the surgery branch, National Cancer Institute, Bethesda, Md.

They described the case of a 50-year-old woman participating in an ongoing phase II clinical trial assessing adoptive transfer of tumor-infiltrating lymphocytes targeting personalized cancer neoepitopes (individualized T-cell therapy). This patient was the only participant to date in whom the treatment induced tumor regression.

A total of 3 of her 10 lung metastases were resected to identify mutations expressed by the tumors, and these were found to express mutant KRAS G12D and HLA-C*08:02. The lymphocyte cultures that reacted most strongly against these antigens were expanded and made into a single infusion, which was administered after the patient had undergone nonmyeloablative conditioning using cyclophosphamide and fludarabine. The patient then received five doses of interleukin-2, which produced the only adverse effect of the entire regimen, fatigue.

At 40-day follow-up, all seven remaining lung metastases showed marked regression. One lesion showed progression at 9-month follow-up and was resected, and the patient has remained cancer free for the subsequent 4 months (N Engl J Med. 2016 Dec 8. doi:10.1056/NEJMoa1609279).

Laboratory analysis of the one metastasis that progressed showed that it had mutated further, losing heterozygosity of the copy of chromosome 6 that encoded HLA-C*08:02. “The presence of this molecule is required for direct tumor recognition by the transferred KRAS G12D-specific T cells. ... [Such a loss] has been observed in human cancers and may represent a hurdle that needs to be overcome to enhance immunotherapeutic efficacy in some patients,” Dr. Tran and his associates wrote.

“In such cases, targeting antigens that are presented by the remaining HLA class I alleles or exploiting the CD4+ T-cell response or the innate immune system against cancer may be necessary to induce a durable clinical response,” they added.