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Tumor infiltrating lymphocyte (TIL) therapy, first pioneered by Dr. Stephen Rosenberg from the National Cancer Institute, isolates immune cells called lymphocytes from a patient’s surgically removed tumor that are then grown in large quantities in the lab. The army of grown TILs are then reinfused back into the patient where they recognize and destroy cancer cells in the body. Prior to the reinfusion, the patient is treated with chemotherapy to deplete all existing lymphocytes. After TIL reinfusion, the patient is treated with a therapy that encourages lymphocytes in the body to grow and divide.

Iovance Biotherapeutics has a proprietary TIL manufacturing process that is being used to develop an individualized TIL therapy called Lifileucel. It is being tested in advanced unresectable or metastatic melanoma patients who have progressed on or after treatment with checkpoint immunotherapy and/or BRAF/MEK targeted therapy. Recent data presented at the Society for Immunotherapy of Cancer (SITC) annual conference demonstrated durable efficacy and a 4-year overall survival rate of 21.9% in this advanced and difficult to treat patient population.³

Included in the above study is a small group of patients with mucosal melanoma, a rare melanoma subtype that develops in the mucous membranes of the body. Mucosal melanoma accounts for only 1% of all melanomas diagnosed and represents a difficult to treat subtype of the disease. Preliminary data was presented by Dr. Evido Domingo-Musibay (Masonic Cancer Center) at the 2023 European Society of Medical Oncology Annual Congress and by Dr. Harriet Kluger (Yale Cancer Center) at this year’s Society for Melanoma Research Annual Congress from 12 patients with advanced mucosal melanoma that were refractory to anti-PD1 treatment. These patients had an overall response rate of 50% (6 out of 12 patients) with durable responses in 4 patients from a single infusion of Lifileucel.⁴ Researchers plan to follow these patients for a number of years to look at the true durability of response.

On March 24th, 2023, Iovance submitted a Biologics License Application (BLA) to the FDA for the approval of Lifileucel. The FDA decision is expected by the end of February 2024.

In addition, a large phase 3 clinical trial is now enrolling patients with untreated melanoma in a study testing the efficacy and safety of lifileucel in combination with pembrolizumab compared with pembrolizumab alone (NCT05727904).

Advancing RARE Registry Insights: The Power of Your Data

The Melanoma Research Alliance is excited to share a poster presentation called RARE: A Registry for Patients with Acral and Mucosal Melanoma which was presented last week at the Society for Melanoma Research (SMR)’s 20^thannual Congress. SMR aims to enhance communication among melanoma researchers by organizing annual research congresses, emphasizing new research results to engage both basic and clinical researchers. In addition, SMR works to promote collaboration among organizations focused on prevention, screening, and surveillance, facilitate partnerships among major research groups, and represent the melanoma research community to the public and funding agencies.

This year's conference, hosted in Philadelphia, PA, had over 600 attendees from around the world. Several members from the MRA staff attended and presented recent RARE Registry data, increasing awareness and interest among clinicians, researchers, and participants.

Just over one year since launch, the MRA team shared updates into how your survey data is taking shape as the RARE Registry grows, illustrating how the synergy of individual data points coalesces into a rich tapestry of knowledge. Participant data is a driving force for future advances in acral and mucosal melanoma research and emphasizes the collective strength of our community. Together, we are not only building a comprehensive understanding of these rare melanomas but also paving the way for more appropriate interventions, improved patient outcomes and disease management, and a brighter future for patients and families facing acral and mucosal melanoma.

Poster attached below (click to open in new window):

During this RARE Registry update, held on August 23 at 12:30 pm ET, de-identified data was shared from the first 100 participants, new participant features were demonstrated, and the MRA team answered questions from participants. Learn more about the RARE Registry at www.raremelanoma.org

 

Despite the tremendous progress made in the last decade in treating melanoma, approximately one third of patients don’t benefit from currently approved therapies. This includes the majority of people with rare forms of melanoma — melanomas that develop in the eye, nailbeds, palms, soles of the feet, and various mucosal membranes. Patients facing these subtypes tend not to respond as well to current treatments as patients with cutaneous melanomas that arise on sun-exposed skin. But as investigators continue to chip away at understanding what causes these melanomas and how they differ from UV-driven cutaneous melanomas, the hope is the better understanding they reap will be sown into improved treatments for these patients. Researchers explored both the challenges and the opportunities for rare melanoma research at the 2021 MRA Scientific Retreat.

New Insights Into the Genetics of Acral Melanoma

Keiran Smalley of H. Lee Moffitt Cancer Center and Research Institute and his MRA-funded team hope to find a genetic ‘smoking gun’ of what causes acral melanoma, a rare subtype of melanoma that develops on the palms, soles of feet, or under finger or toe nails, and comprises about two to three percent of all melanomas. The researchers assumed that, like many cutaneous melanomas, acral melanomas evolve from moles whose growth goes awry due to a series of specific genetic flaws. But this didn’t prove to be so for most of the tissues they analyzed when the researchers genetically compared benign moles from acral sites (feet, hands) to that of acral melanoma tumors. “This surprised us because it suggests it is unlikely that acral nevi [moles] are likely to be the precursors for the majority of acral melanomas,” Smalley said.

Digging deeper, they then mapped out the genetic landscapes of nine acral melanoma samples and found tremendous variability in the genetic material and the ways in which cell functions were altered. Unfortunately, no distinctive genetic signature was found among the samples that could provide a specific target for a drug that might be effective for patients with this rare melanoma. However, the researchers did find a group of genes with altered activity shared among most of the samples. The researchers also noted fewer and less active immune cells in the acral melanoma tumor samples compared to samples from cutaneous melanoma. This suggests that acral melanoma is less likely to spark an immune response and may explain why many patients with this subtype often do not respond to checkpoint immunotherapy, Smalley noted.

Titia de Lange of Rockefeller University, Marcin Imielinski of Weill Cornell, and their research team also found a tremendous amount of variability in the genetic landscape of the acral melanoma samples they studied. Many of these genetic alterations were due to major disruptions in genetic material, akin to typhoons creating piles of genomic wreckage, which break up the chromosomes and reattach the genes on them in new ways. These genetic disruptions are quite different from the smaller number of consistent and more pinpoint genetic changes often seen in cutaneous melanoma on sun-exposed skin. But because of the jumbling and multiplication of genetic material that often occurs after these chromosomal catastrophes, they likely trigger production of new proteins (antigens). The immune system can recognize some of these new tumor antigens and attack the cells that have them when stimulated by checkpoint immunotherapy, the researchers speculate. They suggest that molecular markers for these types of chromosomal disruptions, if present in patients’ tumors, might indicate whether they are likely to respond to such treatments.

UV-Driven Melanomas Extend Beyond the Skin

Richard Marais of the Cancer Research UK Manchester Institute reported on a new discovery that suggests that a subgroup of mucosal melanoma patients could respond to checkpoint immunotherapies or targeted therapies. Most mucosal melanomas arise in areas of the body not exposed to the sun, so lack the telltale genetic changes caused by ultraviolet radiation (UVR) induced DNA damage that are thought to contribute to responsiveness of these melanomas to checkpoint blockade. Mucosal melanomas are also not generally considered to be eligible for BRAF plus MEK inhibitors. However, Marais has found that melanomas arising in the mucosal membrane that covers the eye and lines the inside of eyelids have the distinctive signature common to sun-induced common cutaneous melanoma. These mucosal melanomas also had a high mutation burden and a high incidence of BRAF mutations, suggesting that they are likely to respond to the therapies approved for common cutaneous melanoma. Quoting Nick Hayward’s data, Marais noted that uveal melanomas arising on the iris also bear the telltale genetic signature of sun-induced DNA damage, suggesting that these melanomas may also respond to checkpoint immunotherapies. 

“This makes us start to think about basic concepts in how melanoma is driven,” Marais said, pointing out that the data suggests that melanoma is driven by distinct processes in different parts of the body, but that UVR imprints additional events over the baseline processes to accelerate melanoma development. “We need to apply these findings to develop new treatments for rare melanomas, because responses are driven by the underlying genetics rather than by the tissue of origin” Marais noted, concluding that these findings reinforce public health messages about the importance of protecting the eyes from UVR.