Stanford Medicine delivers first FDA-approved cell-based therapy for solid tumors

In March, Stanford Medicine became the first center in the nation to treat a patient with metastatic melanoma using a new cell-based therapy approved by the Food and Drug Administration. The therapy, which offers hope for people with advanced melanoma whose cancers have resisted immunotherapies, is the first cell-based therapy approved by the FDA to treat solid tumors.

Cell-based therapies — in which immune cells are collected from a patient and treated or genetically modified to enhance their cancer-fighting ability — are not new. Chimeric antigen receptor T-cell therapies, or CAR-T therapies, have been used for several years to fight blood cancers such as leukemias.

The new treatment, which uses immune cells harvested from a patient’s tumor called tumor-infiltrating lymphocytes, exploits the body’s own natural cancer-fighting ability. Once the tumor-infiltrating lymphocytes, or T cells, are harvested, they are encouraged in the laboratory to multiply into billions of cancer-fighting cells, then returned to the patient about a month later.

“These cells are naturally existing T cells that target multiple aspects of the existing tumor,” said 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, which are not genetically modified, CAR-T therapies use genetic engineering to modify a patient’s T cells to recognize and respond to a specific molecule or molecules on the surfaces of cancer cells. Doing so requires researchers to predict which molecules will serve as the best targets — easier for blood cancers than for 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 around the country offering the treatment.

The therapy, called lifileucel and commercially known as Amtagvi, is marketed by San Carlos-based Iovance Biotherapeutics.

Clinical trials of lifileucel for metastatic melanoma that worsened while on standard treatment found that about 30% of 153 patients who received the therapy had their tumors shrink or disappear. Of those, 40% experienced no progression of their cancers for at least 18 months after the one-time infusion.

A quarter-century of research

Tumor-infiltrating lymphocyte therapy was first conceived of in the late 1980s by Steven Rosenberg, MD, PhD, at the National Cancer Institute. In the intervening decades, he and others optimized the treatment and conducted clinical trials exploring its promise. In October, Rosenberg was awarded the National Medal of Technology and Innovation, in part for his role in bringing tumor-infiltrating lymphocyte therapies to the clinic.

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

IL-2 stimulates the cells to divide repeatedly, generating an army of billions. While the cells are growing in the laboratory, the patient undergoes chemotherapy to deplete existing lymphocytes — creating a biological niche for the newly energized cells to further expand when they are returned to the patient.

“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 the cells are returned, the patient is given several doses of IL-2 to further encourage the expansion of the cancer-fighting cells.

The technique works particularly well with melanomas, which are flush with lymphocytes. But Betof Warner and Miklos feel that improvements in the cell-expansion technique may make it useful even for tumors such as lung and colorectal cancers that tend to have fewer infiltrating immune cells — a class of tumor known as “immune cold.”

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

Not every person with metastatic melanoma will qualify for the therapy under the terms of the FDA approval. People 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 the hopes of making 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 the responses based on the lymphocytes found in the tumor. Are they healthy? What molecules on the 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.”

See also:
The promise of TIL Therapy