A strategy to increase the effect of immune checkpoint blockade by targeting retinoic acid signaling in immunosuppressive solid tumors.
Sarcomas are solid tumors with more than 70 rare and often fatal subtypes. Typical survival rates are under 15% over 5 years. Sarcomas can prevent the formation of tumor-killing cells by eluding immune detection, a process termed immunosuppression. These tumors are largely resistant to immune checkpoint blockade (ICB), a cancer immunotherapy which promotes the formation of tumor-killing cells. More effective strategies to target sarcomas are needed.
Recently, Dr. Haldar and his team have found that sarcomas can suppress the immune system through the secretion of retinoic acid (RA), a molecule which favors the formation of immune cells unable to detect tumors. Their latest findings demonstrate that inhibiting the RA pathway in sarcomas triggers a tumor rejection response by directly boosting the formation of tumor-detecting immune cells.
Dr. Haldar’s team has developed a combination therapy to bolster existing immunotherapy against sarcomas that produce high levels of RA. Their protocol combines conventional ICB therapy with molecules that block RA signaling in tumors, an approach found to greatly reduce the size and weight of tumors in mice (see figure). This strategy could enhance survival rates and quality of life for patients with sarcoma.
Blocking retinoic acid (RA) signaling with RA receptor blocker BMS493 potentiates immune checkpoint blockade (ICB) agent anti-PD1 antibody (aPD1) to reduce tumor size in mice. Each line represents an individual mouse.
- Therapy against sarcomas resistant to immunotherapy
- Promising treatment against other cancer types using the RA pathway
- Renders immunotherapy efficient against unresponsive sarcoma subtypes
- Could potentiate other existing treatments such as chemotherapy or radiotherapy
- Could extend lifespan and increase quality of life of affected patients
Stage of Development:
- 2 targets identified: RA synthesizing enzymes and RA receptors
- Preclinical discovery
US Provisional Patent Application
Postow MA et al. J Clin Oncol. 2015 Jun 10;33(17):1974.
Docket # 19-8980