Vaccine Therapy for Cancer: Id2KD Attenuated Whole Tumor Cell Therapeutic Vaccination
- Anthony Sandler, MD
- Lina Chakrabarti, PhD
- Priya Srinivasan, PhD
- Clifford Morgan
Tumor vaccines lack effect, primarily due to poor tumor antigen presentation and immunosuppressive mechanisms exploited by the tumor itself. We explored the use of attenuated live tumor cells as a method for optimal tumor antigen presentation and determined the effectiveness of combining antigen presentation with an immune activating agent (checkpoint blockade).
The inhibitor of differentiation protein 2 (Id2) is found to be a key molecule modulating phenotypic transition in neuroblastoma. Immune-competent as well as immune-compromised mice were challenged with Id2 knockdown Neuro2a (Id2kd-N2a) and tumor growth was monitored for 4-6 weeks. Id2kd-N2a cells were subsequently used for vaccination with or without cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) blockade in a model of established neuroblastoma tumor.
Tumors failed to grow in immunologically competent mice challenged with viable Id2kd-N2a cells, and these mice subsequently developed immunity against further wild-type Neuro2a tumor challenge. Validating the immunologic effect, the Id2kd-N2a cells grew aggressively in SCID and nude immune-compromised hosts. Therapeutic vaccination with Id2kd-N2a cells alone suppressed tumor growth even in established neuroblastoma tumors, and when used in combination with CTLA-4 blockade, large established tumors were eradicated. Furthermore, an increased number of CD8+ T-cells and enhanced production of IFN-gamma was observed in the splenocytes of mice that were cured of tumor. More importantly, a massive infiltration of CD8+ T-cells was found in the shrinking tumors of vaccinated mice.