Eradication of established tumors in mice by a combination antibody-based therapy

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Tumor cell apoptosis is a cornerstone of cancer therapy.
• Tumor-specific T cells are critical for successful antitumor immunotherapies.
• Targeting the TNF-related apoptosis-inducing ligand (TRAIL) receptor DR5 can induce cancer cell death.

Purpose of the Study:

• To investigate the efficacy of a combination therapy involving agonistic monoclonal antibodies against DR5, CD40, and CD137 for cancer immunotherapy.
• To assess the ability of this combination therapy to stimulate tumor-specific effector CD8+ T cells and eradicate established tumors.
• To evaluate the safety and potential for autoimmunity of this therapeutic approach.

Main Methods:

• Treatment of mice with primary fibrosarcomas and metastases using a combination of three agonistic monoclonal antibodies (trimAb): one targeting DR5 and two targeting costimulatory molecules CD40 and CD137.
• Assessment of tumor rejection, tumor cell apoptosis, T cell activation, and cytokine production (e.g., interferon-gamma).
• Evaluation of potential toxicity and induction of autoimmunity.

Main Results:

• The trimAb therapy potently and rapidly stimulated tumor-specific effector CD8+ T cells.
• Established tumors, including those with significant resistance to DR5-targeted therapy, were effectively eradicated without apparent toxicity or autoimmunity.
• Tumor-specific CD8+ T cells producing interferon-gamma were rapidly induced in the tumor-draining lymph node, highlighting their crucial role in tumor rejection.

Conclusions:

• A combination therapy of agonistic antibodies to DR5, CD40, and CD137 is a potent strategy for stimulating tumor-specific CD8+ T cells and achieving tumor eradication.
• This approach effectively eliminates tumors, even those resistant to single-agent therapy, with a favorable safety profile.
• These findings in mice suggest that this rational antibody-based therapy holds significant potential as an effective cancer immunotherapy for humans.