In the ongoing fight against cancer, new and innovative cell-based therapies continually emerge, offering hope and progress where traditional treatments may fall short. Among these groundbreaking approaches is Tumor-Infiltrating Lymphocyte (TIL) therapy, which harnesses the body’s own immune system to target and eradicate cancer cells, representing a remarkable fusion of immunology and oncology. Alongside TIL therapy, other promising cell-based treatments like Chimeric Antigen Receptor-T cell (CAR-T) therapy, Natural Killer Cell (NK-cell) therapy, Dendritic Cell (DC-cell) therapy, and T-Cell Receptor (TCR) therapy have also emerged. Each of these methods utilizes unique aspects of the immune system to identify and eliminate cancer cells, highlighting the diverse array of weapons in the battle against this complex disease. This article explores the scientific principles behind TIL and CAR-T therapy, their various applications, and the collective potential they hold for transforming cancer care.

 

Figure 1. Patient’s killer T cell (left) attacking a cancer cell

Dynamic digital illustration of a T-cell attacking a cancer cell, showcasing glowing orange and blue spherical structures with connecting fibers.

 

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CAR-T, Chimeric Antigen Receptor-T Lymphocyte

People have billions of killer type T cells in their body, and a few are ready to kill each of COVID, tuberculosis, or syphilis-infected cells, an incompatible transplant, or cancer cells.

The CAR-T laboratory construct makes billions of any one type, e.g. designed to kill a particular cancer. Typically, a patent’s T killer cells are purified and their receptor, what they specifically bind to and destroy, is changed to recognize cancer cells and to kill them. The cells are then expanded in the laboratory to billions before returning them to the patient.

The procedure is very successful in leukemias and lymphomas. Since 2017, the Food and Drug Administration (FDA) has approved six CAR T cell products for patients with advanced relapsed or refractory blood cancers
CAT-T therapy works a) only in a subset of patients, b) does not always work in solid tumors, c) initial cost is around $400,000 and ancillary costs of follow up are also considerable.

CAR T cell therapies for solid tumors are not approved. Solid cancers account for 90% of cancer deaths.
Adding IL-10 to CAR-T produces superior efficacy against solid tumors modes in mice. The CAR-T cells resist exhaustion and exhibit enhanced cytotoxicity and proliferation.

TIL, Tumor Infiltrating Lymphocytes

TIL refers to taking lymphocytes from a patient’s solid tumor, growing up billions of cells, and administering them back to the patient. Once reintroduced into the body, these activated T cells (TILs) can migrate from the bloodstream into tumors, where they can identify and attack cancer cells. This is a primitive treatment, meaning that the doctor has no control over what is given to the patient. Only a small fraction of cells may be specific killers of the cancer. Each individual “drug” is different. Collecting T cells from the tumor site means that many are irrelevant and many of the cells are there because they have recognized the presence of specific abnormal proteins, or antigens, on the surface of the tumor cells. Melanoma, one of the hardest cancers to treat, is particularly suited for this procedure because it has the highest rate of accumulating mutations.

TILs were pioneered 30 years ago by Dr. Stephen Rosenberg at the National Cancer Institute, but responses were too erratic to be a usable therapy. In 2024 the Food and Drug Administration (FDA) approved AMTAGVI (generic, lifileucel) for advanced melanoma, previously impossible to treat. This is the first TIL to be accepted as an approved therapy. The drug’s approval was based on findings from a clinical trial sponsored by Iovance Biotherapeutics. Among the 73 participants who were treated with lifileucel dose of at least 7.5 billion cells, nearly one-third had some reduction in the size of their tumors (a tumor response), with tumors disappearing completely (a complete response) in several participants. Moreover, about 40% of those whose cancer responded to lifileucel still had no progression of their cancer a year after receiving the one-time infusion treatment.

Longer-term findings from a larger group of 153 patients were reported in December 2023 at the European Society of Medical Oncology’s (ESMO) 2023 Immuno-Oncology Congress, and they largely mirror the findings from these 73 patients. Of the 48 people (31.5%) whose cancer responded to treatment with lifileucel, more than half have lived at least a year without any evidence of their cancer getting worse. About 10% of these responses are ongoing—that is, there continues to be no evidence that their cancer is getting worse—and nearly all have lasted several years. The longest lasting response is nearly 5 years.

The issue with TIL therapy is a) it costs over $500,000, b) the fraction of patients that respond cannot be identified, and c) considerable monitoring and side-procedure are required.

As part of lifileucel treatment, two measures are taken to enhance the infused TILs ability to attack the cancer. First, patients undergo rounds of high-dose lymphodepleting chemotherapy, to give space for the administered TIL to expand. Second, after the lifileucel infusion, patients are given several doses of IL-2, the primary growth factor for TIL.

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Who will respond to lifileucel? What about side effects?

There are some hints that might help identify who is most likely to respond to lifileucel, Few people responded whose cancer had spread to the brain or liver, which was the case for about half of the 153 patients. Responses were also unlikely in people who had larger tumor burdens—that is, a substantial amount of cancer in their body.

These findings suggest that lifileucel might be most effective if it is given before the cancer has spread to many other parts of the body or individual tumors have become quite large.

All participants in the trial had side effects caused by the treatment, but mostly not dangerous. TIL therapy does not appear to cause the often serious immune-related side effects commonly seen in people treated with CAR T-cell therapy, including cytokine release syndrome and neurologic effects. Patients need to be relatively healthy to receive the therapy, which isn’t always the case for people with advanced cancer who have undergone other treatments. Patients need to have normal heart and lung function.

From clinical trials to using TILs in everyday cancer care

Iovance announced that it has approved more than 50 treatment centers across the United States to collect tumor samples for making lifileucel and administering the final treatment to patients.

After the FDA approval of lifileucel approval for advanced melanoma, what comes next?

Iovance has started enrolling participants in a large trial combining lifileucel with the immunotherapy drug pembrolizumab (Keytruda) as an initial treatment for advanced melanoma. Lifileucel is showing promising tumor responses in people with advanced lung cancer, as well as ovarian and head and neck cancers. That includes complete eradication of tumors in individual patients with advanced colon cancer and advanced breast cancer treated in clinical trials at the NIH Clinical Center.

Researchers have also begun genetic engineering of TILs, with the goal of increasing the number of people who respond to the treatment or eliminating the need for the pre-infusion chemotherapy or post-infusion IL-2.

Metastatic synovial sarcoma: Adaptimmune Therapeutics has received FDA approval for treating this solid tumor target. Of 4 patients, the complete response rate, no evidence of disease, was 4.5%. The partial and complete response rate was 43%.

Combining TIL and CAR-T

The next improvement would be to take TIL, cells that have already responded and homed to the tumor, identify the neoantigen-reactive receptors that are triggered by the cancer, and make CAR-T cells from these. Under Dr. Rosenberg’s direction, 3 of 7 patients with colorectal cancer had clinical responses lasting up to 7 months using this method.

Cell-based potency assays for assessing the effectiveness and quality of cell therapy products

Assessing the effectiveness and quality of cell therapy products like CAR- T, TIL, Tumor-DC, TCR and NK requires robust potency assays tailored to each therapy’s unique characteristics. Some common potency assays used for these cell therapies include:

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