CLL-1 CAR-T cells and trametinib for the treatment of Ras-mutated CMML and JMML
Elliot Stieglitz
MDUniversity of California, San Francisco
Project Term: November 1, 2023 - October 31, 2026
We hypothesize that demonstrating activity of CLL-1 CAR-T (CLL1CART) cell therapy with or without trametinib in pre-clinical models of chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) is the most efficient method to bring cellular therapy to patients with these orphan diseases. In Aim 1, we will determine the in vitro and vivo efficacy of CAR-T cells redirected against CLL-1 using patient-derived xenograft (PDX) models of CMML and JMML. In Aim 2, we will evaluate the role of combining trametinib with CLL1CART cells. Based on our preliminary data, we hypothesize that trametinib will have direct antileukemia activity and will increase the efficacy of CLL1CART by decreasing T-cell exhaustion and augmenting T-cell fitness.
"Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are similar types of blood cancers that both carry poor prognoses. Although these two disorders affect patients at opposite ends of the age spectrum (elderly patients in CMML and infants in JMML) they share several key characteristics. Most importantly, ""Ras"" mutations are found in the most aggressive cases of CMML and in all cases of JMML. The only cure for either CMML or JMML involves a stem cell transplant which is very intensive and causes many side effects. CMML and JMML patients who are eligible for a transplant and survive the potential side effects, still often have their blood cancer return after the transplant. We therefore need to develop newer and safer types of treatments for these patients. “CAR-T” cells use a patient's own immune system to attack and get rid of the cancer cells. CAR-T treatments have had miraculous effects in more common types of leukemia, but it has never been tested in CMML or JMML patients. In this grant, we will test CAR-T therapy in mouse models of CMML and JMML. We will also combine CAR-T therapy with an oral medication called trametinib, which has shown promise in both CMML and JMML patients. Based on our research, we hypothesize that adding trametinib will directly kill leukemia cells and also improve the function of co-administered CAR-T cells. With funds from this innovative LLS mechanism, we will test CAR-T cells in the laboratory using “pre-clinical” models of CMML and JMML in order to demonstrate their effectiveness with a short-term goal of bringing this innovative combination therapy to CMML and JMML patients.
Due to the similarities between CMML and JMML, there is a strong rationale to study these two diseases together. We have assembled a team of leading CMML/JMML physician-scientists with expertise in CAR-T cells and trametinib, all of whom have designed, conducted and completed clinical trials. We believe that we can leverage each other’s expertise to accomplish the goals set out in this grant."