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Universal Platform for Localized Solid Tumor Cancer Immunotherapy

Therapeutics

Project Overview

Solid tumors, particularly aggressive forms like triple-negative breast cancer (TNBC), present significant challenges in oncology. Unlike hematological cancers, which have seen remarkable success with chimeric antigen receptor T (CAR T) cell therapy, solid tumors remain difficult to treat. TNBC, which lacks specific therapeutic targets, is especially challenging, with high rates of metastasis and poor long-term outcomes. Current treatments, including chemotherapy and immunotherapy, often fail to achieve durable responses, leaving patients with limited options.

The limitations of CAR T cell therapy in solid tumors stem from several factors:

CAR T cell Homing: Poor trafficking of CAR T cells to the tumor site.
Hostile TME: Immunosuppressive environments that inactivate and exhaust CAR T cells.
Tumor Heterogeneity: Insufficient recognition of diverse tumor cells.
Safety Concerns: Risks such as cytokine release syndrome and off-target toxicities.

To address these challenges, Thanh Barbie, MD, Assistant Professor of Surgery at Harvard Medical School and Dana-Farber, and her colleagues at Dana-Farber have developed a universal platform for localized cancer immunotherapy. This platform leverages an FDA-approved polyethylene glycol (PEG) hydrogel biopsy marker to deliver immunotherapeutic agents directly into the TME, essentially priming it for local delivery of CAR T cells and offering a novel approach to treating solid tumors.

Technology

The platform is built on the foundation of an FDA-approved PEG hydrogel biopsy marker, commonly used in breast cancer diagnostics. This marker, which resembles a grain of rice, contains a metal clip for radiographic visibility and a hydrogel matrix that Dr. Barbie discovered is capable of absorbing and releasing therapeutic agents. The hydrogel’s unique properties—biocompatibility, long-term stability in human tissue (up to 11 months), and lack of foreign body reaction—make it an ideal vehicle for localized drug delivery.

The platform enables the sequential delivery of immunotherapeutic agents, including:

STING Agonists: Stimulator of interferon genes (STING) agonists activate innate immune responses within the TME. The hydrogel marker allows for sustained, localized release of STING agonists, overcoming the rapid clearance and systemic toxicity observed in previous clinical trials.
CAR T Cells: CAR T cells are engineered to target specific tumor antigens. By injecting CAR T cells directly into the hydrogel marker, the platform ensures their localized release into the TME, enhancing their efficacy and reducing systemic side effects.
Combination Therapy: The platform supports the co-delivery of small molecules, such as STING agonists, along with CAR T cells, creating a synergistic effect that primes the TME for robust anti-tumor activity.

Extensive preclinical studies in mouse models of TNBC have demonstrated the platform’s efficacy:

Intratumoral CAR T Expansion: CAR T cells delivered via the hydrogel marker showed robust expansion within the tumor, as visualized by bioluminescence imaging.
Tumor Growth Inhibition: In TNBC models, localized delivery of CAR T cells significantly inhibited tumor growth.
Enhanced CAR T Efficacy with Preconditioning: Preconditioning the TME with a STING agonist (ADU-S100) before CAR T cell delivery enhanced CAR T cell expansion and prevented tumor relapse.
Systemic Effects: The platform not only eradicated primary tumors but also controlled distant metastatic lesions and blocked the formation of new metastases. This suggests the induction of systemic immune memory, potentially preventing recurrence.
Safety: Localized delivery mitigated the systemic toxicities commonly associated with STING agonists and CAR T cell therapy.

The development of a universal platform for localized cancer immunotherapy represents a paradigm shift in the treatment of solid tumors. By leveraging the unique properties of an FDA-approved PEG hydrogel biopsy marker, this approach overcomes the barriers that have limited the success of CAR T cell therapy in solid cancers. Preclinical studies have demonstrated its potential to eradicate primary tumors, control metastatic disease, and induce systemic immune memory, all while minimizing systemic toxicities.

Team Members: Thanh Barbie, MD, David Barbie, MD

Applications

The universal platform has broad implications for cancer treatment, particularly in addressing the limitations of current therapies for solid tumors.

Triple-Negative Breast Cancer (TNBC): The platform is particularly well-suited for TNBC, where it addresses the limitations of current therapies and offers a targeted approach to both primary and metastatic disease. By combining STING agonists and CAR T cells, the platform offers a promising approach to treating both primary and metastatic TNBC. The ability to deliver therapy locally minimizes systemic side effects, improving patient quality of life.

Other Solid Tumors: The platform’s versatility makes it applicable to a wide range of solid cancers, including melanoma, lung cancer, and pancreatic cancer. The key is identifying tumor-specific antigens for CAR T cell targeting.

Metastatic Disease: The ability to control distant metastases and prevent new lesions makes the platform valuable for treating metastatic cancers. Multiple hydrogel markers can be implanted to target different metastatic sites.

Combination Therapies: Beyond STING agonists and CAR T cells, the platform can be adapted to deliver small molecule therapeutics and other immunotherapeutic agents, such as natural killer (NK) cells, immune checkpoint inhibitors, and additional immune agonists.

Minimally Invasive Procedures

The platform’s reliance on an FDA-approved biopsy marker simplifies its clinical translation. The marker can be implanted using minimally invasive techniques, such as image-guided biopsy, making it accessible to a wide range of patients. This approach is particularly advantageous for oligometastatic disease, where localized treatment of metastatic sites can significantly improve outcomes.

Opportunities

Dana-Farber is looking for collaboration opportunities to support first-in-human clinical development at Dana-Farber.

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