Sequential CAR T cell and targeted alpha immunotherapy in disseminated multiple myeloma

Area of Science:

• Oncology
• Immunotherapy
• Radiotherapy

Background:

• Multiple myeloma (MM) remains incurable despite advances in antibody and cellular therapies.
• Monotherapies targeting single antigens have limited efficacy, with most patients relapsing.
• Sequential immunotherapies targeting different antigens may offer improved outcomes.

Purpose of the Study:

• To evaluate the preclinical therapeutic potential of sequential immunotherapy combining targeted alpha therapy (TAT) against CD38 and CAR T cell therapy against CS1 in a systemic MM model.
• To compare the efficacy of CAR T therapy followed by TAT versus TAT followed by CAR T therapy.

Main Methods:

• Preclinical studies utilizing a systemic multiple myeloma model.
• Sequential administration of ²²⁵Ac-DOTA-daratumumab (anti-CD38 TAT) and CS1-targeted CAR T cell therapy.
• Comparison of different sequences and timings of TAT and CAR T cell therapy.
• Evaluation of survival benefit compared to monotherapy and untreated controls.

Main Results:

• CAR T cell monotherapy improved median survival from 49 days to 71 days.
• Sequential therapy (CAR T followed by 7.4 kBq TAT) increased median survival to 106 days (from 47 days in controls), significantly outperforming CAR T monotherapy (68 days).
• Untargeted TAT showed minimal improvement over CAR T monotherapy, highlighting the importance of tumor targeting.
• The timing of sequential therapies was crucial for optimal efficacy.

Conclusions:

• Sequential targeted immunotherapies, including CD38-targeted TAT and CS1-targeted CAR T cells, demonstrate significant promise over monotherapies for multiple myeloma.
• The order and timing of sequential treatments are critical factors for maximizing therapeutic benefit.
• These findings support further investigation of combined immunotherapies for refractory multiple myeloma.