SUPPRESSION OF MYELOID DERIVED SUPPRESSOR CELLS AND IMMUNE CHECKPOINT BLOCKADE

• Main Authors: Zhou, Shibin, Kinzler, Kenneth W, Vogelstein, Bert, Kim, Kibem
• Format: Patent
• Language: English
• Published: 25.02.2021
• Subjects: CHEMISTRY; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PEPTIDES; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES

Impressive responses have been observed in patients treated with checkpoint inhibitory anti-PD-1 or anti-CTLA-4 antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Treatment with both anti-PD-1 and anti-CTLA-4 antibodies were unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. However, co-treatment with epigenetic modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of them. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K-inhibitor that reduced circulating MDSCs also cured 80% of mice with metastatic 4T1 tumors when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.