New Approach Using mRNA Generates Cellular Immunotherapy Within the Body

Chimeric antigen receptor T-cell therapy, or CAR T, has revolutionized the treatment of blood cancers. The single infusion of genetically modified immune cells has led to durable remissions for patients with few to no other treatment options. However, CAR T has not been as successful in solid tumors, and researchers continue to investigate methods to make it more viable for patients.

One approach being evaluated focuses on macrophages rather than T cells as carriers of CARs to help bolster an anti-tumor immune response. Macrophages are monocytic and tissue originated innate immune cells, identifying and responding to foreign pathogens. Previous studies have shown that CAR-M therapy, which like CAR T uses a patient’s own cells that are genetically engineered to target a specific tumor antigen for treatment, is well tolerated and efficacious in cancers with HER2 overexpression.

Now, scientists are taking that idea one step further. Carisma Therapeutics and Moderna have developed a novel version of CAR-M therapy that does not require a patient’s cell. The cellular immunotherapy delivers modified messenger RNA (mRNA) encapsulated into lipid nanoparticles to generate CAR-M that target primarily macrophages (plus monocytes, and dendritic cells) within tumor hosts. When infused in the body, the therapy redirects the function of myeloid cells, which are recruited by tumors to promote growth, to recognize tumor-associated antigens and trigger anti-tumor responses without signs of toxicity.

Dr. Paulo Rodriguez, Chair, Department of Immunology

Preclinical proof of concept results presented at the Society for Immunotherapy of Cancer annual meeting demonstrate that this in vivo CAR-M therapy approach can work for solid tumors, such as advanced lung and pancreatic cancers.

“Regional and systemic administration of CAR-encoding mRNA/LNP led to significant tumor regression in subcutaneous and systemically disseminated metastatic solid tumor models,” said Dr. Paulo Rodriguez, chair of the Immunology Department at Moffitt Cancer Center. “These data demonstrate that CAR-M can be directly produced in vivo and directed against tumor associated antigens using mRNA/LNP technology.”

It is important to note the in vivo CAR-M therapy has not yet entered human clinical trials.