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Published on: March 5, 2010
CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma
Monica Casucci1, Benedetta Nicolis di Robilant, Laura Falcone
1Leukemia Immunotherapy Group, San Raffaele Scientific Institute, Milan, Italy;
Abstract:
Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.
Insights
Genetically engineered T cells targeting CD44v6 show promise for treating acute myeloid leukemia (AML) and multiple myeloma (MM). This approach effectively eliminates cancer cells while allowing for safe ablation if needed, paving the way for clinical trials.
Area of Science:
- Immunotherapy
- Oncology
- Cell Therapy
Background:
- Adoptive T-cell therapy faces challenges in feasibility and efficacy for cancer treatment.
- Identifying broadly expressed tumor targets essential for growth can overcome limitations and prevent immune escape.
- CD44 variant 6 (CD44v6) is a receptor implicated in the cancer stem cell phenotype across various tumor types.
Purpose of the Study:
- To investigate the potential of genetically targeted T cells against CD44v6 for treating hematologic malignancies.
- To assess the efficacy and safety of CD44v6-targeted T cells in preclinical models of acute myeloid leukemia (AML) and multiple myeloma (MM).
- To evaluate the utility of a coexpressed suicide gene for controlling T-cell activity and mitigating toxicity.
Main Methods:
- Silencing of CD44v6 to assess its role in AML and MM engraftment in immunocompromised mice.
- Development and testing of chimeric antigen receptor (CAR) T cells targeting CD44v6 against primary AML and MM cells.
- In vitro activation protocols (CD3/CD28 beads, IL-7/IL-15) and in vivo efficacy assessments.
- Coexpression of a suicide gene for inducible ablation of CD44v6-targeted T cells.
Main Results:
- Silencing CD44v6 inhibited the engraftment of human AML and MM cells.
- CD44v6-targeted CAR T cells demonstrated potent antitumor activity against primary AML and MM, sparing normal hematopoietic stem cells and keratinocytes.
- In vitro activation was crucial for in vivo antitumor efficacy.
- Coexpression of a suicide gene allowed for rapid pharmacologic ablation of T cells, preventing xenogeneic graft-versus-host disease and toxicity.
Conclusions:
- CD44v6 is a viable target for T-cell-based immunotherapy in AML and MM.
- Suicidal CD44v6-targeted T cells offer a potentially safe and effective therapeutic strategy.
- These findings support the clinical investigation of this approach for treating AML and MM.
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