On February 2, 2023 CoImmune, Inc., a clinical stage immuno-oncology company working to redefine cancer treatment using best-in-class cellular immunotherapies, reported that preclinical models show CAR T cells engineered with OrexiCAR technology to secrete a CD47-SIRPα checkpoint blocker have improved anti-tumor activity and reverse myeloid immunosuppression in tumors (Press release, CoImmune, FEB 2, 2023, View Source [SID1234626799]). The results are published in Blood, the most highly cited peer-reviewed publication in the field of hematology.
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The work was directed by David Scheinberg, M.D., Ph.D., Chairman of the Sloan Kettering Institute’s Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center (MSK). Dr. Scheinberg and colleagues invented the OrexiCAR technology that is licensed to CoImmune. Researchers engineered CAR T cells to locally secrete a high affinity CD47-blocker, CV1, at the tumor site (OrexiCAR T cells), and treated human lymphoma-bearing xenograft mice in combination with an orthogonally targeted monoclonal antibody (rituximab).
Results demonstrate that OrexiCAR T cells plus rituximab were additive in effect on lymphoma tumor regressions and mouse survival without new toxicities:
80 percent of mice treated with OrexiCAR T cells had no detectable tumor at day 86 post tumor engraftment, as compared to only 25 percent treated with wild type CAR T cells, in conjunction with rituximab.
Mice treated with OrexiCAR T cells had significantly improved median overall survival compared to those treated with wild type CAR T cells in combination with rituximab or CV1 plus rituximab.
OrexiCAR-secreted CV1 reversed tumor immunosuppression of myelomonocytoid cells, both in vitro and within the tumor microenvironment.
OrexiCAR T cells were not toxic in mice.
"While traditional CAR T therapies have reported high response rates in hematopoietic cancers, we also see a high level of relapses and a relative lack of efficacy in solid tumor settings due to multiple tumor escape mechanisms including the overexpression of CD47," said Charles Nicolette, Ph.D., Chief Executive Officer of CoImmune. "We are collaborating with MSK to engineer these technologies into our CAR-CIK platform to deliver additional agents locally to tumor sites to mitigate tumor escape by loss of targeted antigens and tumor induced immunosuppression. We now have an exciting opportunity to advance the science of immunotherapy with fundamentally new approaches to broadly target a range of cancers that have been up to now largely refractory."
In October 2021, CoImmune acquired the rights to several technologies developed at MSK including Synthetic Enzyme-Armed Killer (SEAKER) cells that combine the target-seeking power of immune cells with the ability to locally generate a potent anticancer drug at the tumor site without systemic toxicity, also referred to as a "micropharmacy."
"This research proves that human T cells can be engineered to co-express both a CAR and a CD47 checkpoint blocker while maintaining T cell function, and that we can simultaneously equip T cells with a secondary orthogonal mechanism for activating the immune system," said Dr. Scheinberg. "Importantly, the local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and should prevent systemic toxicities. This combination of CAR T cell therapy, local CD47 blockade, and orthogonal antibody may be a strategy to overcome the limitations of tumor antigen loss and heterogeneity and immunosuppression of the CAR T cell."