OmniCAR cells and binders will be manufactured and tested by the...

OmniCAR cells and binders will be manufactured and tested by the ECLIPSE team headed by Jeffrey Molldrem, M.D., professor and chair ad interim of Hematopoietic Biology and Malignancy at MD Anderson.

I wonder whether this collaboration will link into Jeffrey Molldrem’s Anti-PR1 Immune Therapy for Myeloid Leukemia project.

Molldrem’s team has identified the TCR-like antibody, 8F4, as having specificity for PR1, a desirable target antigen in AML. However, antibodies for the treatment of cancer, including leukaemia, have limited effectiveness as single agents. The Molldrem team at M D Anderson hypothesise that modifying T cells with an 8F4-CAR could more effectively eliminate AML, and potentially some other cancers as well.

The long-term goal of this project is to develop immune therapies that target aberrantly expressed proteases in blasts and leukemia stem cells. The investigators identified a T cell receptor (TCR)-like antibody (8F4) with specificity for a conformational epitope of PR1 (VLQELNVTV), a peptide derived from leukemia-associated protease antigens (LAAs) P3 and NE, that are bound to HLA-A2. 8F4 induces complement-dependent cytolysis (CDC) of AML and leukemia stem cells (LSC) and inhibits AML progenitor cell growth but not normal bone marrow progenitors, which supports further study of 8F4 as a potential therapeutic monoclonal antibody for AML……

While studies of 8F4 appear promising, a significant reduction of LSC required prolonged treatment with 8F4 in PDX-bearing mice. Antibodies for the treatment of cancer, including leukemia, have limited effectiveness as single agents. Also, additional studies in PDX models showed that 8F4 treatment of some primary AML resulted in the growth of a population of blasts with low PR1 expression but without changes in overall HLA-A2 expression. This potential mechanism of 8F4 resistance or escape suggests that increasing the potency of 8F4-based therapy will be important for its successful clinical application….

The investigators hypothesize that AML will be more effectively eliminated by redirecting polyclonal T cells to target PR1/HLA-A2, by modifying T cells with an 8F4-CAR, or with treatment using an 8F4xCD3 bispecific antibody….

If successful, this project will result in a completely novel immunotherapeutic strategy in the form of 8F4 monoclonal antibody or cellular therapies that may benefit cancers expressing this target. This is not only applicable to AML, but also to other cancers, e.g. breast and lung cancer, which cross-present the PR1 target antigen and are susceptible to 8F4 killing.

https://www.mdanderson.org/research/departments-labs-institutes/spores/leukemia-spore/research.html