A team of researchers from Sanford Burnham Prebys Medical Discovery Institute (CA, USA) have reported that the combined administration of immune checkpoint inhibitors and tumor necrosis factor (TNF) can eradicate tumors in a mouse model of medulloblastoma.
The authors of the study, published in Nature Neuroscience, hope that the success of their combinatorial immunotherapy approach can be replicated in pediatric clinical trials.
The study involved two mouse models with medulloblastoma, one with mutations in the p53 gene and one without. Gene expression experiments allowed them to identify that tumor cells not expressing p53 did not express MHC-I proteins.
Expression of MHC-I proteins is required to allow tumor cells to be recognized and targeted by the immune system.
“Our findings suggest that some cancers may not respond to immunotherapy because the tumors don’t have sufficient MHC-I levels to trigger an effective immune response,” commented senior author, Robert Wechsler-Reya (Sanford Burnham Prebys).
The next step for the researchers was to promote expression of MHC-I in the mutant p53 medulloblastoma mouse model. This was achieved by administration of low doses of TNF.
Consequent use of immune checkpoint inhibitors prolonged survival and promoted tumor removal, even resulting in complete eradication of cancerous tissue in some mice.
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“This work suggests that adding TNF to immunotherapy could benefit medulloblastoma patients with tumors lacking p53,” explained first author of the study, Alexandra Garancher (Sanford Burnham Prebys). “If p53 is missing, low doses of TNF may boost MHC-I to the levels needed for immunotherapy to work.”
The effectiveness of the combination immunotherapy was also tested in a mouse model of diffuse intrinsic pontine glioma, another pediatric tumor with a fatality rate of almost 100%. In the study, approximately half of the mice receiving a combination of TNF and immune checkpoint inhibitors survived.
The next step for the researchers is to test their combination immunotherapy against medulloblastoma in a Phase I clinical trial.
“Our hope is that in the near term, combining immunotherapy with TNF will increase the effectiveness of immunotherapy for children who are battling brain cancer,” concluded Wechsler-Reya. “We look forward to testing this approach in the clinic and are hopeful that this discovery might be able to save children’s lives.”
Sources: Garancher A, Suzuki H, Haricharan S et al. Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma. Nat. Neurosci. doi:10.1038/s41593-020-0628-4 (2020) (Epub ahead of print); www.sbpdiscovery.org/news/scientists-identify-promising-immunotherapy-combination-for-pediatric-brain-cancer