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Immunotherapy, which boosts the immune system’s ability to find and kill cancer cells, has revolutionized how melanoma is treated. Several types of immunotherapies are FDA-approved and currently available for patients or are being developed in clinical trials. However, immunotherapy can stop working (called refractory) or never provide an initial response to patients. New treatments are being studied that aim to last longer and that work in more people, including those with refractory cancer.1,2
One type of immunotherapy uses cells rather than drugs to treat the cancer. The biotechnology company Immatics is developing a T cell receptor (TCR) cell therapy called anzu-cel (anzutresgene autoleucel, formerly IMA203). TCR T-cell therapy is a type of cancer immunotherapy that uses a patient’s own immune cells, called T cells, to treat cancer. T cells are obtained and extracted from a patient’s blood, modified in the lab to better recognize and attack cancer cells, grown in the lab to increase their numbers, and then infused back into the patient. Anzu-cel is a one-time cell therapy designed to help a patient’s own immune system find and destroy melanoma cells. This approach takes advantage of a cancer-specific molecule called preferentially expressed antigen in melanoma (PRAME) and an immune protein called HLA-A*02:01.
To learn more about anzu-cel and the clinical trials testing this treatment, we talked to Dr. Justin Moser, medical oncologist and associate clinical investigator at HonorHealth Research Institute and associate research professor at Arizona State University John Shufeldt School of Medicine and Medical Engineering in Scottsdale, Arizona.
Human leukocyte antigen (HLA) is a genetic marker that helps the immune system tell the difference between the body’s own cells and potentially harmful ones, like cancer cells. Anzu-cel is designed to work in patients who have a specific HLA type called HLA-A*02:01. Dr. Moser commented that this is the most common HLA subtype.
PRAME is a protein found in more than 50 cancers, including nearly all melanomas. PRAME is rare in normal cells.3 Therapies that target PRAME are expected to mainly attack cancer cells and have minimal effects on normal cells.
For Immatics’ anzu-cel approach, immune cells called T cells are collected from the patient’s blood. T cells have a protein on their surface, known as a TCR, that allows them to recognize and bind to molecules on the surface of cancer cells. But not all T cells have or are equipped with the right TCR to recognize and fight the cancer cells. With anzu-cel, the collected T cells are modified to carry a TCR that is optimized to recognize PRAME plus HLA-A*02:01 on the surface of melanoma cells. The modified TCR on the T cell connects to HLA-A*02:01/PRAME on the cancer cell – like a key fits into a lock. “When this happens and the two cells are close to each other, the T cell attacks the melanoma cell like it was an infection and kills the melanoma cell,” explained Dr. Moser.
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Immatics is testing anzu-cel in a phase III trial called SUPRAME (NCT06743126). This trial is currently recruiting and is testing if anzu-cel works better than standard of care in patients with advanced melanoma, including cutaneous, acral, or melanoma of unknown primary previously treated with and have disease progression (resistance or toxicity) on an anti-PD-1 therapy. Participants who are HLA-A*02:01 positive and PRAME positive are randomized to anzu-cel or standard treatment. Standard treatment options are nivolumab plus relatlimab (Opdualag®), lifileucel (Amtagvi®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), ipilimumab (Yervoy®), or chemotherapy.
The phase III SUPRAME trial is supported by results from a phase Ib trial (NCT03686124) that examined anzu-cel in various solid tumors.4 Of the 14 patients with cutaneous melanoma, 50% (7 patients) responded at least partially to the treatment (their tumors shrank or disappeared). Of the 15 patients with uveal melanoma, 67% (10 patients) responded at least partially. Responses to anzu-cel lasted a median of 1 year, with some patients showing an ongoing response that has lasted more than 32 months so far. Anzu-cel was safe and tolerable to patients, with side effects such as low blood counts and immune-related effects that were anticipated due to the way the treatment works.
To receive anzu-cel, patients need to be HLA-A*02:01 positive, which is determined with a blood test. Eligible patients undergo an outpatient procedure called leukapheresis - in which T cells are collected from their blood. The T cells are sent to Immatics, which modifies them to recognize PRAME plus HLA-A*02:01 on cancer cells. Millions of these modified T cells are grown in the lab. Before the modified T cells can be infused into the patient, the patient undergoes a short course of chemotherapy to prepare the body to receive the cells. Then, the cells are infused into the patient in a single dose. The patient is also given a low-dose of Interleukin-2, which activates the immune system and supports the infused cells. Chemotherapy, infusion, and initial monitoring occur in the treatment center. These steps can take up to a few weeks. The research team continues to monitor the patient after release from the hospital.
Dr. Moser explained that patients tend to tolerate this treatment well. The dose of chemotherapy and the dose of IL-2 are lower than what is needed for another type of cell therapy called TIL therapy. Dr. Moser noted that for this reason, “more patients, such as those who are older or less fit, can receive anzu-cel.”
The side effects with anzu-cel include low blood cell counts, low hemoglobin, and low platelets, which could require a blood transfusion. Other side effects include inflammatory syndromes such as cytokine release syndrome and a neurological condition called ICANS, both of which involve the immune system acting too aggressively. These conditions are all treatable and manageable.
Dr. Moser explained that responses to anzu-cel and other cell therapies can be long-lasting. “What’s unusual is that the patients who responded to anzu-cel were refractory to standard immunotherapies,” he said. “The observations of a high response rate and responses that are long-lasting in refractory patients are really exciting.”
Dr. Moser would like patients to know that “anzu-cel is an option if your cancer hasn’t responded or has become refractory. You can begin screening and cell collection while you are on your current treatment if you and your doctor think you might need it in the future. You don’t have to wait until you’re in need of a new treatment. You can start the process of screening and be poised to take action sooner.”
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