Tumor Regression and Cure Depends on Sustained Th1 Responses

Area of Science:

• Immunology
• Oncology
• Cancer Therapy

Background:

• Immunomodulatory monoclonal antibodies (mAbs) show therapeutic potential against tumors but rarely achieve complete cures.
• Optimizing combination therapies is crucial for improving patient outcomes in cancer treatment.

Purpose of the Study:

• To evaluate the efficacy of novel combinations of immunomodulatory mAbs, with and without cisplatin, in a TC1 mouse lung carcinoma model.
• To investigate the immunological mechanisms underlying tumor regression and relapse following mAb treatment.

Main Methods:

• Established subcutaneous TC1 tumors in mice were treated intratumorally with weekly doses of mAb combinations (e.g., CTLA4/PD1/CD137, CTLA4/PD1/CD137/CD19).
• The combination of CTLA4/PD1 mAbs with intraperitoneal cisplatin (10 mg/kg) was also tested.
• Immune responses in tumor-draining lymph nodes and spleens were analyzed, focusing on T-cell responses and macrophage polarization.

Main Results:

• Combinations of 3 or 4 mAbs (targeting CTLA4, PD1, CD137, and optionally CD19) induced complete regression of both treated and untreated tumors.
• Tumor cure correlated with a shift from Th2 to Th1 immune responses, involving memory T cells and M1 macrophages.
• Combining CTLA4/PD1 mAbs with cisplatin led to long-term complete regression in most mice, particularly with smaller tumors; efficacy improved with larger tumors when cisplatin was added to 3 or 4 mAb combinations.

Conclusions:

• Multi-antibody combinations, especially with cisplatin, can achieve complete tumor regression and long-lived immunity in a preclinical model.
• Tumor relapse is associated with a return to a Th2 microenvironment, not the emergence of immune-resistant cells.
• The size of the tumor impacts the efficacy of immunomodulatory therapies, highlighting the need for potent combination strategies.