Immunotherapies are increasingly recognized as potential cures for advanced cancer. Tumor-infiltrating lymphocyte (TIL) therapy expands a patient’s TIL cells to create a more robust response when administered back to the patient. TIL therapy targets multiple tumor antigens, making it especially advantageous for treating solid tumors compared to currently available gene-engineered T cell therapies. Success has been achieved in treating melanoma patients with TIL therapy, but other cancers have not been explored with this therapy.
Gynecologic cancers have been identified as promising targets for TIL therapy. For example, because cervical cancer is closely associated with human papillomavirus infection, it provides ideal tumor-specific antigens to target with TIL therapy. In 2022, there were over 1.4 million new cases of gynecologic cancers globally, highlighting the need for new cancer immunotherapies.
Immunotherapy for Gynecologic Cancers
A new study, published in The Journal of Immunology, investigated methods for expanding tumor-reactive TILs from gynecologic cancers (ovarian, endometrial, and cervical) and explored genetic engineering approaches to enhance TIL proliferation and survival.
Gynecologic TILs expanded more efficiently with anti-CD3 monoclonal antibody and CD28 co-stimulation than with the traditional IL-2-based incubation used for melanoma. While PD-1 is an established marker of tumor-reactive CD4+ and CD8+ T cells, PD-1 expression negatively affects T cell proliferation. “We suggest that CD28 co-stimulation is essential to overcome the T cell function impaired by PD-1 signaling,” said Dr. Yuki Kagoya, Professor at Keio University School of Medicine and lead author.
Genetic Engineering of TIL Cells
The researchers also found that providing cytokine signaling through genetic engineering served as a safe and effective method to enhance TIL persistence and antitumor activity. This was compared to the high-dose of IL-2 used in traditional protocols, which can induce significant toxicity in patients, such as systemic capillary leak syndrome.
“In the future, genetic engineering of TILs will be essential to fundamentally reprogram exhausted TILs and enhance their durability and antitumor efficacy. We hope our methodology provides a ready-to-use protocol for efficient expansion of TILs from gynecologic and potentially other types of cancers,” shared Dr. Kagoya.
The researchers plan to build on this work by exploring genetic targets to comprehensively reinvigorate TIL function using CRISPR or cDNA library-based screening, which will be essential for the long-term efficacy of TIL therapy.
The Journal of Immunology (The JI), published by the American Association of Immunologists is one of the most highly cited journals in the field of immunology. The JI is committed to describing novel findings in all areas of experimental immunology, including basic and clinical studies.
