ONCY reovirus study accomplishes a "first" in CRC treatment
This the first time that immune insensitive microsatellite stable (MSS) tumors that account for 85% of all colorectal cancer (CRC) can be effectively converted to immunotherapy sensitive cancers by introducing reovirus.
MSS colorectal cancer (CRC) tumors are poorly immunogenic and largely resistant to immunotherapy, necessitating a need to develop new immune enhancing strategies. Oncolytic reovirus has a high propensity to replicate in KRAS mutant tumors which account for ~50% of MSS CRCs.
The current study explored the ability of reovirus to potentiate the effect of immune checkpoint inhibition in MSS CRC and demonstrated that reovirus promotes an overall inflammatory TME and increases the responsiveness of MSS tumors to immunotherapy.
Furthermore, reovirus significantly enhanced the anti-tumor activity of anti-human PD-1 [nivolumab] treatment in MSS CRC cell lines ex vivo.
Combinatorial reovirus/anti-PD-1 treatment reduced the tumor proliferative index, increased apoptosis of the cancer cells and differentially altered PD-L1/PD-1 signaling among CT26 [MSS, KRASMutated ] and MC38 [MSI, KRASWild type]tumors.
Activation of innate immune system and expression of PRRs and antigen presentation markers were observed under reovirus and anti-PD-1 treatment that additionally reduced immunosuppressive macrophages. This led to an increase in T cell subsets, increase in effector T cell activation, and decrease in exhaustion markers specifically within CT26 microenvironment.
Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems
Authors: Titto Augustine, Peter John, Tyler Friedman, Jeeshan Jiffry, Hillary Guzik, Rifat Mannan, Riya Gupta, Catherine Delano, John M. Mariadason, Xingxing Zang, Radhashree Maitra, Sanjay Goel
https://www.biorxiv.org/content/10.1101/2021.09.03.458915v1.full