Tumor-Infiltrating Lymphocytes: A New Weapon Against Melanoma

Tumor-infiltrating lymphocytes are a troop of battle-hardened soldiers

Lymphocytes are an important component of the immune system that help the body fight off infections and eliminate diseased cells. Lymphocytes, made up of T cells and B cells, are highly skilled migrators that effectively navigate and scan almost all parts of the body (immune surveillance) to eliminate abnormal cells, including cancer.

However, tumor-targeting T cells are unable to make their way out of the bloodstream to penetrate the tumor and attack cancer cells. Over the past few years, cancer drugs harnessing the power of the patient’s immune system have tried, with some success, to get around this impediment, and altered the paradigm of cancer care in the process. This is particularly true of melanoma –the first cancer to be targeted by immune checkpoint inhibitors. Thanks to recent strides in immunotherapy, melanoma deaths are declining. Recent approval of CAR-T cells by the US Food and Drug Administration has encouraged scientists to advance their knowledge even further about immunotherapy with the hope of developing CAR-T cell therapies for a range of blood and solid cancers.

Still, effective treatment options are limited for patients with metastatic melanoma, and they do not experience a long-term disease-free survival even after the remarkable success of immune checkpoint inhibitor therapy. In a recent study on a group of patients with melanoma treated with immune checkpoint inhibitors, more than 40% of the patients developed long-term immune-related side effects. Recently, it has been shown that adoptive cell therapy of melanoma-derived T cells produces durable clinical responses and significant tumor regression. This indicates the need for better immunotherapy for more effective melanoma treatment.

Tumor-infiltrating lymphocytes as stealth fighters

Tumor-infiltrating lymphocytes (TILs) are the specialized T cells from the immune system that are found in tumors. These TILs are a collection of lymphocytes that have fought their way through the connective tissue and blood vessels surrounding the tumor. Once in the tumor, the tumor-infiltrating lymphocytes begin to kill cancer cells. However, the killing spree is not left unchecked. Sometimes they are prevented by signals from the tumor that applies brakes in the immune system to weaken the response. Immune checkpoint inhibitors have been successfully developed to block some of the brakes and unleash the immune response to attack cancer cells. However, the response rate is very limited with solid tumors, which paved the way for developing alternative therapeutic strategies.

Tumor-infiltrating lymphocyte therapy involves the extraction of T cells from metastatic lesions to specifically target an antigen derived from tumor-specific mutations or neoantigens. These fighter T cells (isolated from a patient who recognizes tumor-specific neoantigens) are expanded in the lab to form the TILs infusion product. This product is then infused back into the patient’s blood following chemotherapy to deplete the suppressive immune cells that allow preferential repopulation of the tumor-infiltrating lymphocytes to fight cancer. Unlike CAR-T cells, which are genetically engineered to recognize one or two targets, TILs recognize multiple targets on the cancer cells as they come from the tumor. This approach offers a therapeutic advantage because it recognizes targets that are masked by a broad array of immunosuppressive mechanisms inside the tumor microenvironment. TILs hold promises for highly personalized treatment of solid tumors that are not effectively treated by CAR-T cells. However, tumor-infiltrating lymphocytes have certain limitations. The tumor must be large enough to be surgically removed, and it takes about a month to isolate TILs and expand them in the lab to get billions of cells for infusion, which limits their use in a patient with late-stage cancer.

Tumor-infiltrating lymphocyte immunotherapy has not been approved yet, but has demonstrated efficacy in multiple single-center trials against malignant melanoma or advanced solid tumors. In a Phase II study, Lifileucel, a one-time tumor-infiltrating lymphocyte adding up to more than 1 billion TILs, has shown safety and efficacy in patients with metastatic melanoma that progressed despite treatment with immune checkpoint inhibitors. FDA has granted Lifileucel a Regenerative Medicine Advanced Therapy designation, an Orphan Drug designation, and a Fast-Track designation for advanced melanoma. There have been many TIL studies with encouraging results. As of today, there are 33 interventional studies (Phase I and II) recruiting patients in the US for various cancers (including melanoma, lung, breast, cervical, head, and neck cancer) using autologous TILs (ClinicalTrials.gov). The results of these trials will guide the FDA in the approval of TILs for clinical use.

The blog post was written by Arif Azam Khan, PhD, an Immunology Scientist at Charles River’s Bothell, WA site. Arif brings extensive research experience in human T and B cell immunobiology for target identification and preclinical exploratory studies. In his current role, he is actively involved in the development and production of antigen-specific T cells and specialized immune cells for research in I-O, autoimmunity, cell therapy, and the infectious disease domain.