Pioneering firsts in solid tumor cancer therapy

Penn Medicine is a world-renowned center for cell and gene therapy, including extended indications for certain solid tumors such as sarcoma and melanoma. Penn’s ability to offer these innovative therapies on an accelerated timeline after approval is possible because of Penn’s institutional expertise, clinical resources, and advanced technologies. Early adoption at Penn Medicine also serves as a gateway to wider use of novel innovative therapies in the general medical community.

This article reviews the introduction of lifileucel and afami-cel at Penn Medicine. Lifileucel and afami-cel are first-in-class therapies to treat melanoma and synovial sarcoma, respectively.

A clinical leader in melanoma therapy and research

In 2014, researchers in the Perelman School of Medicine discovered that hypofunction of tumor-infiltrating lymphocytes (TILs) can limit the efficacy of CAR T cells in solid tumors, including melanoma. The loss of function was reversible when the T cells were isolated away from the tumor, and was suspected to be the result of upregulation of intrinsic T-cell inhibitory enzymes and the expression of surface inhibitory receptors.

Lifileucel, the first personalized cell therapy in solid tumors, offers hope for advanced melanoma

Lifileucel was the first immunotherapy to earn FDA approval for the management of solid tumors. Approved in February 2024 and made available at Penn Medicine immediately thereafter, lifileucel is indicated for the treatment of adults with unresectable or metastatic melanoma who have progressed on immune checkpoint inhibitors and BRAF/MEK inhibitors.

A groundbreaking advance, lifileucel is a personalized autologous tumor-infiltrating lymphocyte (TIL) immunotherapy. Tumor-bound lymphocytes, which have an innate capacity to target a broad array of tumor surface antigens, are isolated from a resected tumor specimen. Once collected and isolated, these TILs are expanded into billions of cells in the presence of other agents.

After these T cells are infused, they migrate to the tumor site and infiltrate tumor tissue. Patients receive lymphodepleting chemotherapy before infusion and several doses of IL-2 shortly thereafter to enhance TIL potency. Lymphodepletion diminishes the presence of Tregs, myeloid-derived suppressor cells, and other suppressive immune elements, thereby establishing a more permissive environment for infused TILs to expand and function.

The FDA granted accelerated approval for lifileucel based on the findings of a multicenter study (C-144-01) in patients with unresectable or metastatic melanoma who progressed following ≥1 prior systemic therapy with either a PD-1 blocker or a BRAF inhibitor with or without MEK inhibition.

The objective response rate in this trial was 31.4% with a median time to response of 1.4 months and a median duration of response of 36.5 months. Nearly one-third of responders (31.3%) completed the five-year assessment with ongoing responses. The median overall survival was 13.9 months with a five-year survival rate of 19.7%. Survival outcomes were consistent among responders, regardless of time of onset of response to therapy.

Lifileucel is available at Penn Medicine for eligible patients with advanced and metastatic melanoma that has not responded to other immunotherapy drug treatments.

Afami-cel, the first T cell receptor gene therapy for adults with unresectable or metastatic synovial sarcoma

Afamitresgene autoleucel is the first FDA-approved T cell receptor (TCR) gene therapy for the treatment of adults with unresectable or metastatic synovial sarcoma (SS), a rare soft tissue sarcoma that primarily affects adolescents and young adults. About half of patients with SS develop recurrent or metastatic disease following standard of care therapy.

Like tisagenlecleucel (tisa-cel), afami-cel is an autologous T-cell immunotherapy created by extracting and genetically engineering a patient’s own T cells, then reinfusing them as a single intravenous dose. However, while tisa-cel modifies T cells to target the CD19 protein on B cells, afami-cel-modified T cells express a TCR that targets MAGE-A4, an antigen expressed by cancer cells in SS.

In order to receive afami-cel, individuals must have received prior chemotherapy, possess at least one HLA-A*02 antigens, and have tumors expressing the melanoma-associated antigen MAGE-A4.

Daniel Lefler, MD, Clinical Director of Penn Medicine’s Sarcoma Program and Assistant Professor of Clinical Medicine in the Division of Hematology Oncology, noted that patients treated with afami-cel had a 30% chance of not needing further treatment after two years—a result unheard of in the world of sarcoma.

Afami-cel has the potential to greatly enhance quality of life for patients with SS. The value of giving a patient a one-time treatment and allowing them a ‘holiday’ from ongoing chemotherapy cannot be understated, Dr. Lefler notes, because it means that patients don't need treatment every three or four weeks, or a pill that's making them feel sick. “This is a big quality of life consideration in terms of time off from treatment for these patients,” he adds.

Afami-cel was FDA-approved on the basis of the Phase 2 SPEARHEAD-1 trial, in patients with advanced, unresectable, or metastatic synovial sarcoma who had received prior chemotherapy. In this trial, afami-cel demonstrated an overall response rate (ORR) of 43.2% (complete response rate of 4.5% and partial response rate of 38.6%), with a median duration of response of 6 months. Of note, ~37% of patients received the drug tocilizumab to treat cytokine release syndrome (CRS). Tocilizumab, a monoclonal IL-6 receptor antagonist, was FDA approved in 2017 for the treatment of CAR T cell-induced CRS on the basis of studies performed in 2014 at the Abramson Cancer Center and Children’s Hospital of Philadelphia.

A leader in cellular therapy, Penn Medicine’s Abramson Cancer Center is an authorized treatment center for afami-cel.

Clinical consultations and patient referral

To refer a patient to the Penn Medicine Division of Hematology and Oncology, call 877-937-7366 or refer a patient online.