“Personalized” Immunotherapy Appears Effective in Small Study of Patients With Metastatic Solid Tumors

A new cellular immunotherapy technique that combines features of a well-known personalized therapy used in blood cancers and tumor-infiltrating lymphocyte (TIL) therapy, used to treat metastatic melanoma, showed promise in a small trial of patients with metastatic colorectal cancer (CRC), according to results published Thursday in Nature Medicine.¹

If successful, this would be the first time since TIL therapy was used in melanoma that any cellular therapy has worked in a solid tumor, according to Steven A. Rosenberg, MD, PhD, of the National Cancer Institute’s Center for Cancer Research (CCR), a co-lead investigator of the study.

Steven A. Rosenberg, MD, PhD, is the co-lead investigator of a study of a personalized immunotherapy technique published in Nature Medicine. | Image credit: National Cancer Institute

In blood cancers, the concept of harvesting cells from patients and modifying them through a genetic engineering process to attack cancer has been used for more than a dozen years, since patient Emily Whitehead was first treated with CAR T-cell therapy for acute lymphoblastic leukemia in 2012. Her treatment, tisagenlecleucel (Kymriah), was approved by FDA in 2017.2 Although several other CAR T-cell treatments have been approved for blood cancers since that time, investigators have not succeeded in transferring this approach to solid tumors.

In this new NCI study, investigators used normal white cells, or lymphocytes, from each patient and genetically modified them to create receptors designed to recognize and attack individual cancer cells. For the patients with CRC in this study, this personalized immunotherapy reduced tumors and kept them from regrowing for up to 7 months, according to the findings in Nature Medicine.¹

“The fact that we can take a growing metastatic solid cancer and get it to regress shows that the new cellular immunotherapy approach has promise,” Rosenberg said in a statement from the National Institutes of Health, which includes NCI.³ “However, it’s important to understand that these findings are preliminary and that the approach needs to be further refined and tested in more types of solid cancers.”

Rosenberg and his colleagues collected lymphocytes from the tumors in each patient. As described in their abstract, they isolated “unique, personalized, neoantigen-reactive T cell receptors” the lymphocytes that had been present in the tumors. After genetically sequencing the receptors, the researchers used a retrovirus to place genes for the TCR into normal lymphocytes gathered from individual patients’ blood.

As Rosenberg explained, “By taking the natural T-cell receptors that are present in a very small number of cells and putting them into normal lymphocytes for which we have enormous numbers—a million in every thimbleful of blood—we can generate as many cancer-fighting cells as we want.”

As part of a phase 2 trial (NCT03412877), patients treated with this experimental cell therapy first received pembrolizumab, and then afterward received IL-2, another immunotherapy. Results showed that 3 patients had reductions of tumors in the lung, liver, and lymph nodes, which lasted 4 to 7 months (median, 4.6 months).

All patients received T cell populations containing at least 50% of the genetically modified receptor cells which were detected in the peripheral blood of 5 patients, including the 3 who had responses, at levels of at least 10% of CD3+ cells 1 month after receiving the cell therapy. In 1 patient who responded, about 20% of CD3+ peripheral blood lymphocytes expressed the modified receptor cells more than 2 years after treatment.

The study suggests that adoptive cell transfer with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers, the investigators wrote.

References

1. Parkhurst M, Goff SL Lowery FJ, et al. Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results. Nat Med. Published online July 11, 2024. https://doi.org/10.1038/s41591-024-03109-0
2. FDA approval brings first gene therapy to the United States. News release. FDA newsroom. August 30, 2017. Accessed July 12, 2024. https://www.fda.gov/news-events/press-announcements/fda-approval-brings-first-gene-therapy-united-states
3. Immunotherapy approach shows potential in some people with metastatic solid tumors. News release. National Institutes of Health. July 11, 2024. Accessed July 12, 2024. Immunotherapy approach shows potential in some people with metastatic solid tumors | National Institutes of Health (NIH)