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Roswell Park Clinical Trials Offer Novel Immunotherapies for Advanced/Metastatic Tumors, Refractory Melanoma

Clinical trials launched recently at Roswell Park Comprehensive Cancer Center — one exclusive to Roswell Park and the other offered at only eight sites nationwide — focus on new approaches.

Phase 1/1b clinical trial evaluates WTX-124, designed to harness and boost the power of cytokines

Two main challenges have restricted the potential of the cytokine-based immunotherapy interleukin 2 (IL-2): first, its short half-life limits tumor exposure, and second, it can bind to receptors in peripheral tissues, resulting in treatment-associated side effects.

Werewolf Therapeutics hopes to overcome those challenges with the introduction of WTX-124, their proprietary IL-2 INDUKINE molecule currently being evaluated in a phase 1/1b clinical trial at Roswell Park and seven other sites in the U.S. The molecules are engineered to extend the half-life of the cytokines so they remain in circulation and extend the time of tumor exposure.

They are also designed to reduce toxicity by preventing the cytokines from binding to receptors in healthy tissue. However, once inside the tumor microenvironment, tumor-specific proteases activate the INDUKINE molecules to trigger native signaling pathways to induce a pro-inflammatory, targeted anti-tumor response. At this point, the activated cytokine reverts to its original brief half-life so it will clear from the body rapidly.

Igor Puzanov, MD, MSCI, FACP, Senior Vice President, Clinical Investigation; Director, Center for Early Phase Clinical Trials; Chief, Early Phase Clinical Trials Division; and Chief, Melanoma Section at Roswell Park, serves as site principal investigator at Roswell Park for a dose-escalation clinical trial (NCT05479812) that is evaluating WTX-124 both as a monotherapy and in combination with pembrolizumab (Keytruda) in patients with select advanced or metastatic solid tumors.

“These patients face a very poor prognosis,” says Dr. Puzanov. “WTX-124 represents a new approach to immunotherapy that we hope will overcome the limitations of previous cytokine-based therapies.”

Preliminary monotherapy data from a proof-of-mechanism phase 1/1b clinical trial, reported in November 2023 at the annual meeting of the Society for Immunotherapy of Cancer (SITC), showed that WTX-124 generated dose-dependent biomarker and anti-tumor activity in patients with relapsed or refractory advanced or metastatic solid tumors, and that it was generally well tolerated.

Merck Sharp & Dohme LLC are collaborators on the study, which aims to recruit 150 patients. 

Phase 2 trial combines dendritic cell vaccine with modulation of tumor microenvironment, aimed at overcoming PD-1/PD-L1 resistance

A phase 2 clinical trial exclusive to Roswell Park (NCT04093323) is currently recruiting patients with HLA-A2+ refractory melanoma. Researchers hope to determine whether a unique combination of a specialized dendritic cell vaccine and a chemokine-modulating regimen (CKM) — which reprograms the tumor microenvironment (TME) for enhanced entry of vaccination-induced immune effector cells — can prevent the growth and/or induce regression of melanoma tumors that have become resistant to standard immunotherapy. CKM includes interferon alpha (IFN?), which can disrupt the division of cancer cells and slow tumor growth; rintatolimod (Ampligen), which stimulates the immune system; and the pain reliever celecoxib (Celebrex). The goal is to produce a multi-modal attack on the tumor, with the dendritic cells carrying a payload of antigenic peptides that target blood vessels in the tumor.

The clinical trial is led by Dr. Puzanov, principal investigator, with Pawel Kalinski, MD, PhD, Chair, Department of Immunology, Chief of Translational Immuno-Oncology and Senior Vice President for Team Science at Roswell Park, as laboratory lead. Dr. Kalinski also is the holder of a five-year, $14.5 million National Cancer Institute-funded Program Project Grant involving Roswell Park, the University of Pittsburgh Medical Center and Mt. Sinai School of Medicine that has led to the development of this form of immunotherapy for melanoma, breast, ovarian and colon cancers.

Dr. Kalinski provided scientific leadership for a previous clinical trial led by Shipra Gandhi, MD, Assistant Professor of Oncology in the Department of Medicine at Roswell Park, demonstrating that CKM attracted cytotoxic T lymphocytes (CTLs) to tumors in patients with metastatic triple-negative breast cancer, which is expected to prime the immune system to make the tumors more susceptible to the immunotherapy pembrolizumab (Keytruda). The current trial builds on those findings, adding a specialized DC vaccine to induce even more tumor-killing CTLs, and tests the clinical efficacy of the combination treatment.

“We hope the information gleaned from this clinical trial will lead to advances that will enable more patients to benefit from some of the most commonly prescribed immunotherapies,” says Dr. Kalinski.

The National Cancer Institute is collaborating with Roswell Park on this study, which expects to enroll 24 patients.

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