DNA vaccines against GPRC5D synergize with PD-1 blockade to treat multiple myeloma
Praveen Neeli1, Perry Ayn Mayson A Maza2, Dafei Chai2
1Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. neelipraveen@gmail.com.
Abstract:
Multiple myeloma (MM), a hematological malignancy of the bone marrow, remains largely incurable. The orphan G protein-coupled receptor, GPRC5D, which is uniquely expressed in plasma cells and highly expressed in MM, is a compelling candidate for immunotherapy. In this study, we investigated the efficacy of a combination of DNA vaccine encoding mouse GPRC5D and PD-1 blockade in preventing and treating MM using the 5TGM1 murine model of MM. The mouse vaccine alone was effective in preventing myeloma growth but required PD-1 antibodies to inhibit established MM tumors. We next evaluated the prophylactic and therapeutic efficacy of a nanoplasmid vector encoding human GPRC5D in several murine syngeneic tumor models. Similar results for tumor inhibition were observed, as human GPRC5D-specific T cells and antibodies were induced by DNA vaccines. Taken together, these findings underscore the potential of GPRC5D-targeted DNA vaccines as versatile platforms for the treatment and prevention of MM.
Insights
This study shows DNA vaccines targeting GPRC5D can prevent and treat multiple myeloma (MM). Combining GPRC5D vaccines with PD-1 blockade effectively inhibited established MM tumors in mice.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Multiple myeloma (MM) is a fatal hematological cancer with limited treatment options.
- G protein-coupled receptor class C group 5 member D (GPRC5D) is highly expressed in MM plasma cells, making it a promising immunotherapy target.
Purpose of the Study:
- To investigate the efficacy of DNA vaccines encoding GPRC5D, alone and in combination with PD-1 blockade, for preventing and treating multiple myeloma.
- To evaluate both prophylactic and therapeutic potential using murine models.
Main Methods:
- Utilized a 5TGM1 murine model of multiple myeloma.
- Administered DNA vaccines encoding mouse and human GPRC5D.
- Combined GPRC5D DNA vaccination with PD-1 blockade therapy.
- Assessed tumor growth inhibition and immune responses, including T cell and antibody induction.
Main Results:
- GPRC5D DNA vaccine alone prevented myeloma growth in mice.
- Established MM tumors required combination therapy with GPRC5D vaccine and PD-1 blockade for inhibition.
- DNA vaccination induced GPRC5D-specific T cells and antibodies in murine models.
- Nanoplasmid vectors encoding human GPRC5D showed similar tumor inhibition efficacy.
Conclusions:
- GPRC5D-targeted DNA vaccines demonstrate potential for both prevention and treatment of multiple myeloma.
- Combination therapy with PD-1 blockade enhances therapeutic efficacy against established MM.
- GPRC5D DNA vaccines represent a versatile platform for MM immunotherapy development.
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