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Epitope Editing Enables Targeted Immunotherapy of Acute Myeloid Leukemia

An epitope engineering approach to overcome immunosuppression and toxicity by genetically engineering hematopoietic cells.

  • Therapeutics

Project Overview

  • Target molecules are often shared between cancer cells and healthy hematopoietic stem/progenitor cells (HSPCs), leading to immunosuppression and severe hematopoietic toxicity when targeted.
  • Consequently, there is an unmet need for therapeutic strategies that can selectively target cancer cells without harming normal cell populations.
  • Scientists at Dana-Farber have devised an innovative epitope engineering approach to overcome immunosuppression and toxicity by genetically engineering healthy hematopoietic cells.
  • Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset and supporting clinical trials.

Technology

Advancements in gene transfer technology have revolutionized immunotherapy by enabling the reprogramming of immune cells to target molecules expressed on cancer cells. The approval of the first adoptive cellular immunotherapy, CD19 CAR-T cells, for treating B lymphoblastic leukemia marked a significant milestone. However, extending this success to other hematological malignancies like acute myeloid leukemia (AML) and multiple myeloma (MM) has been challenging. This is primarily because potential target molecules are often shared between cancer cells and healthy hematopoietic stem/progenitor cells (HSPCs), leading to immunosuppression and severe hematopoietic toxicity when targeted. Consequently, there is an unmet need for therapeutic strategies that can selectively target cancer cells without harming normal cell populations.

Dr. Pietro Genovese at Dana-Farber Cancer Institute has developed an innovative epitope engineering approach to overcome immunosuppression and toxicity by genetically engineering healthy hematopoietic cells, such as HSPCs and/or T cells, to modify gene-encoding cell-surface proteins. By introducing precise amino acid substitutions in the extracellular domains of FLT3, CD123, KIT, and CD38 in healthy HSPCs using base editing technology, they were able to prevent the binding of therapeutic antibodies and CAR T cells to these antigens on healthy HSPCs without disrupting their normal function. This was achieved through comprehensive epitope mapping and library screening, which identified specific mutations that abrogate antibody recognition while preserving protein activity and regulation. This genetic modification effectively shields healthy cells from antibody-mediated targeting.

Additionally, chimeric antigen receptors can be designed to target the native FLT3, CD123, KIT and CD38 on cancer cells. The genetically modified T cells expressing these CARs can discriminately bind to cancerous but not healthy cells, selectively eliminating cancer cells expressing wild-type FLT3, CD123, KIT, and CD38 while sparing the mutated healthy cells. In combination with the epitope engineering of HSPCs, a dual genetic engineering approach allows for effective cancer cell eradication with minimal toxicity to non-cancerous hematopoietic cells. In Dr. Genovese’s lab, upon treatment with antigen-specific CAR T cells, the sparing of human HSCs was observed in the bone marrow of mice engrafted with edited HSPCs compared to controls.

Further Details:

Casirati, G, Cosentino, A, Mucci, A, et al. Epitope editing enables targeted immunotherapy of acute myeloid leukaemia. Nature 621:404-414 (2023).

Team Members: Pietro Genovese, PhD, Gabriele Casirati, MD, PhD

Applications

  • Enhancement of existing anti-KIT, anti-FLT3, anti-CD123, or anti-CD38 therapies, such as daratumumab, by reducing off-target effects on healthy HSPCs, thereby minimizing hematopoietic toxicity.
  • Development of safer and more effective CAR-T cell therapies for acute myeloid leukemia and multiple myeloma by reducing off-target effects on healthy HSPCs.
  • Application of this dual-engineering strategy to other shared cell-surface proteins in various cancers.

Opportunities

Dana-Farber Cancer Institute is looking for the right partner with an interest in licensing this asset and supporting clinical trials.

Get in touch

Team Members

Pietro Genovese, PhD

Principal Investigator, Department of Pediatric Oncology, Dana-Farber

Assistant Professor of Pediatrics, Harvard Medical School