Treating Advanced Melanoma with Tumor Infiltrating Lymphocyte (TIL) Therapy

Many patients with advanced melanoma (or, metastatic melanoma) have benefited from the new treatments approved by the FDA including immune checkpoint inhibitors and combination BRAF/MEK inhibitors. However, not every patient’s melanoma responds to these drugs, and their disease progresses and tumors continue to grow. 

Immune system cells are often present in and near melanoma tumors. Although these immune cells have recognized the cancer cells and are trying to kill them, their presence alone may not be enough to completely get rid of the tumor. 

Immunotherapy is a treatment strategy that aims to boost the immune system’s ability to recognize and kill cancer cells. Adoptive cell therapy, also called cell-based therapy, is a type of immunotherapy that uses cells to treat cancer (note that adoptive cell therapy can be combined with drug treatment). 

For advanced melanoma, several types of adoptive cell therapy are available or being tested in clinical trials, including tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor-T cells (CAR-T cells), and natural killer (NK) cells. TIL therapy and CAR-T cell therapy involve surgery to remove the tumor, isolation of immune cells (called lymphocytes) from the tumor, modification of the lymphocytes to boost their ability to find and kill that patient’s melanoma cells, and then injection of those cells back into the patient. To learn more about TIL therapy for advanced melanoma, we talked to Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Tampa, Florida.

MRA has played a critical role in supporting research for TIL therapy for melanoma by funding studies conducted by Dr. Hwu and Jeffrey Weber, MD, PhD*. Other work funded by MRA and conducted by Antoni Ribas, MD, PhD and Anusha Kalbasi, MD, as well as Cristina Puig Saus, PhD, is focused on CAR-T cell therapy for melanoma. MRA is also supporting a phase I clinical trial (NCT05629546) testing NK cell therapy in advanced melanoma that will begin soon.

Here we focus on TIL therapy for advanced melanoma. The FDA has approved TIL therapy called lifileucel (Amtagvi®) for patients with melanoma that cannot be removed with surgery or that is metastatic (stage 4) who were previously treated with immunotherapy called a PD-1 blocking antibody and a BRAF inhibitor (if BRAF^V600 mutation positive). 

• For TIL therapy, the patient’s lymphocytes are separated from a tumor sample. Because the lymphocytes are already present in the tumor and likely recognize the tumor as something that needs to be destroyed, lymphocytes are obtained from the tumor rather than the blood. 
• The lymphocytes are grown in the lab to greatly increase their numbers. 
• During this time, which takes several weeks, the patient continues to receive appropriate treatment for their cancer¹. The patient is given drugs to deplete the rest of their lymphocytes, making room for the tumor-fighting lymphocytes. 
• Then the tumor-fighting lymphocytes that were grown in the lab are infused back into the patient along with an immune molecule called interleukin-2 that helps the lymphocytes grow and survive.

One study by Dr. Hwu and colleagues showed that after 10 years, 84% of patients who responded to TIL therapy during the first year continued to be free of disease progression, showing that the effects of TIL therapy can last a long time¹. The patient journey shared below illustrates the potential for TIL therapy to treat advanced melanoma.

Patient journey: Jamie Goldfarb

Jamie Goldfarb had a history of stage 2 and stage 3 melanoma, both of which were treated successfully. However, her melanoma returned as stage 4, with tumors in her liver and pancreas. Jamie and her husband knew about the importance of clinical trials through their work, and so Jamie knew participating in a clinical trial might be a great option for her. After consulting with doctors, Jamie decided to enroll in a clinical trial that was testing TIL therapy.

TIL therapy typically includes administration of an immune-activating drug called interleukin-2. Study investigators continue to test new ways to make TIL therapy safer and more effective. Jamie’s clinical trial used a different strategy in which her TILs that were grown in the lab were engineered to express a different immune system molecule called interleukin-12. For the first few months after receiving TIL therapy, her tumors were growing. However, 4 months after receiving the treatment, Jamie could feel her tumors shrinking, and 2 years after receiving TIL therapy, she was declared cancer free.

Discussion

This patient’s journey illustrates the potential effectiveness of TIL therapy to treat advanced melanoma. For TILs to be most effective, high enough numbers of the right TILs need to be grown in the lab, the lymphocytes need to find the cancer cells, and they need to kill the cancer cells. Challenges at each of these steps are being addressed:

• Selective growth of the best tumor-reactive lymphocytes is an important goal. 
• Researchers are using advanced technology such as CRISPR and gene modification to make the lymphocytes they grow work better.
• The time needed to grow high enough numbers of TILs needs to be reduced.
• Penetration of TILs into solid tumors is low, and TILs need to live a long time in a patient’s body to provide long-term tumor killing and survival benefit to the patient. Scientists are looking for ways to allow TILs to survive the harmful environment in tumors and thus live longer. Dr. Hwu explained that strategies to increase lymphocyte penetration into tumors and enhance the killing ability of lymphocytes include methods that block molecules called VEGF and TGF-beta.
• The toxic effects of the treatment on the patient need to be reduced.
• Methods are needed to treat patients with melanoma that has spread to the brain who currently cannot receive TIL therapy^{1, 2}. 
• TIL therapy is also a complex process that requires specialized expertise². However, Dr. Hwu noted that the FDA-approved TIL therapy is becoming available in more locations.

Another important consideration is understanding who will benefit from TIL therapy. Dr. Hwu stated that about 25-40% of patients respond to TIL therapy. An active area of investigation is identification of biomarkers that will tell doctors if a patient is likely to respond to TIL therapy or not. Dr. Hwu reported that a single biomarker is not informative enough, and a combination of biomarkers will likely provide the best information. Artificial intelligence is being used to help select the most informative set of biomarkers.

Dr. Hwu stated that “the current FDA-approved TIL therapy is the 1.0 version. TIL therapy is just getting started and is only going to get better.” He would like patients to know that “TIL therapy provides hope for patients for whom other treatments didn’t work. Patients should be evaluated for TIL therapy—the earlier the better.”

MRA is leading these efforts to improve the effectiveness of TIL therapy and other cell-based therapy approaches by funding research by Drs. Hwu and colleagues³, as well as other teams.

*Note that Dr. Jeffrey Weber died in August 2024 after his own battle with a different type of cancer. MRA gratefully acknowledges Dr. Weber’s decades of research dedicated to leveraging immunotherapy for melanoma and improving outcomes for people with advanced melanoma.