Newly Published Pre-Clinical Data Show Intratumoral Injections of Messenger RNA Encoding Three Immune Modulators Stimulate Durable Anti-Cancer Responses in Treated and Distal Tumors
Published in Science Translational Medicine, study demonstrates mRNAs encoding IL23, IL36γ and OX40L can activate immunologically “cold” tumor microenvironments
Moderna’s mRNA-2752 (the “Triplet”) now in an ongoing Phase 1 study as a monotherapyand in combination with checkpoint inhibitors in patients with advanced or metastatic solid tumors or lymphoma
The study, published in the scientific journal Science Translational Medicine, found that the local delivery of mRNA encoding the secreted cytokines IL23 and IL36γ and the membrane-bound T-cell co-stimulator OX40L, induced a broad immune response promoting tumor regression in both injected lesions and distant un-injected tumors in mice. When combined with checkpoint inhibitors, mRNA-2752 boosted complete response rates in immunosuppressive and in immunologically barren tumor models that are otherwise unresponsive to checkpoint inhibitors.
“These pre-clinical data are important because they show how we can
utilize multiple mRNAs encoding for immune modulators in a single
therapy to activate a robust, systemic immune response against cancer in
immunosuppressive and in so-called ‘cold’ tumors that are resistant to
checkpoint inhibitors,” said
“Unlike conventional biologics, we believe mRNA therapies can uniquely
alter the tumor microenvironment to make cancers more susceptible to
checkpoint inhibitors via a paracrine effect by producing high, local
therapeutic concentrations of membrane-bound and secreted
immunomodulators, both of which are believed to play a critical role in
the immune response against cancer,” said
The study showed that in a MC38-R mouse cancer model that is considered immunosuppressive and found to be unresponsive to checkpoint inhibitor immunotherapy, a single dose of the Triplet administered intratumorally led to complete responses (defined as the absence of all detectable cancer). After multiple injections in the immunosuppressive tumor model, complete response rates increased to a majority of the treated animals. In addition, a single dose of the Triplet led to near-complete control of both injected tumors and distal untreated tumors. The addition of anti-PD-L1, anti-PD-1 or anti-CTLA-4 checkpoint inhibitors to a single dose of the Triplet improved complete response rates over either mRNA or antibody treatment alone.
A link to the publication, Durable anti-cancer immunity from intratumoral administration of IL-23, IL-36γ and OX40L mRNAs (S. L. Hewitt, et. al.), can be found here.
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amended including, but not limited to, statements concerning: the belief
that mRNA therapies can uniquely alter the tumor microenvironment to
make cancers more susceptible to checkpoint inhibitors and play a
critical role in the immune response against cancer, and the potential
for mRNAs encoding for immune modulators to ignite a robust, systemic
immune response against cancer in immunosuppressive and tumors resistant
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