South SFV Today

Stanford Medicine has recently become the first center in the United States to administer a new cell-based therapy, approved by the Food and Drug Administration (FDA), to a patient with metastatic melanoma. This innovative therapy, which provides hope for patients with advanced melanoma resistant to immunotherapies, is the first FDA-approved cell-based treatment for solid tumors.

Cell-based therapies are not a novel concept. They involve collecting immune cells from a patient and treating or genetically modifying them to enhance their cancer-fighting abilities. Chimeric antigen receptor T-cell therapies (CAR-T therapies) have been utilized for several years to combat blood cancers such as leukemias.

The new treatment uses immune cells known as tumor-infiltrating lymphocytes, harvested from a patient's tumor. These cells are encouraged in the laboratory to multiply into billions of cancer-fighting cells before being returned to the patient about a month later.

"These cells are naturally existing T cells that target multiple aspects of the existing tumor," explained Assistant Professor of Medicine Allison Betof Warner, MD, PhD. "Before now, there was no approved therapy for people with melanoma whose cancers had progressed after immunotherapy and/or targeted therapy. Now we can bring the promise of cell therapy to these patients."

In contrast to tumor-infiltrating lymphocytes, CAR-T therapies use genetic engineering to modify a patient’s T cells so they recognize and respond to specific molecules on cancer cell surfaces. Predicting which molecules will serve as optimal targets is easier for blood cancers than solid tumors.

"We are very excited to move cell-based therapies beyond blood cancers," said David Miklos, MD, PhD, Professor of Medicine and Chief of Bone Marrow Transplantation and Cellular Therapy. "This has been a long time coming, but now we have a new standard of care for these patients."

Stanford Medicine is one of fewer than 30 centers across the country offering this treatment. The therapy, known as lifileucel and commercially marketed as Amtagvi by San Carlos-based Iovance Biotherapeutics, has shown promising results in clinical trials. Approximately 30% of 153 patients with metastatic melanoma that worsened while on standard treatment saw their tumors shrink or disappear after receiving the therapy. Of these, 40% experienced no progression of their cancers for at least 18 months following the one-time infusion.

Tumor-infiltrating lymphocyte therapy was first conceived in the late 1980s by Steven Rosenberg, MD, PhD, at the National Cancer Institute. Over the subsequent decades, he and others optimized the treatment and conducted clinical trials to explore its potential. In October, Rosenberg received the National Medal of Technology and Innovation for his role in bringing tumor-infiltrating lymphocyte therapies to clinics.

The treatment process involves removing a sample of the tumor and collecting any T cells it contains. These cells have already infiltrated and started to fight the tumor, presumably by recognizing a variety of molecules on cancer cell surfaces. The T cells are grown in a laboratory for about one month in the presence of a growth-promoting immune molecule called IL-2.

"Normally, when you remove a tumor from a patient with cancer, you throw it away," Miklos said. "But these trials have shown that the lymphocytes that tumor contains are gold. Your body is already trying to fight these cancers. We’re just helping it out."

After being returned to the patient's body, several doses of IL-2 are administered to further encourage expansion of cancer-fighting cells.

Researchers worldwide are now conducting clinical trials of tumor-infiltrating lymphocytes in other solid cancers including non-small cell lung cancer, advanced colorectal and breast cancer. Other trials are investigating combining lifileucel with immunotherapy as a first-line treatment for advanced melanoma.

However, not every person with metastatic melanoma will qualify for the therapy under the terms of the FDA approval. Patients need to be relatively healthy with good heart, kidney, and lung function and able to withstand the preparative immune-depleting chemotherapy given before the infusion. They also must have seen their cancers worsen while on immunotherapies or targeted treatment that are currently the standard of care for these cancers.

Betof Warner estimates that, of the 8,000 to 10,000 or so people diagnosed with advanced melanomas each year in the United States, about 2,000 people will qualify if patients are identified appropriately and referred to authorized treatment centers.

The researchers are also investigating which molecules the tumor-infiltrating lymphocytes are targeting, with hopes of developing even more targeted treatments.

"We study the tumor that we remove from the patient, as well as the cells we return to the patient and compare that with the patient’s clinical response," Betof Warner said. "Eventually we hope to predict and improve responses based on lymphocytes found in the tumor. Are they healthy? What molecules on cancer cells are they targeting? Although there is more to learn, we are excited to have another option, another line of treatment for these advanced cancers."