Personalized neoantigen-specific adoptive T cell therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS)
Valentina Ferrari1, Alison Tarke1, Hannah Fields1, Luca Ferrari1, Trevor Conley1, Franco Ferrari1, Jie-Hua Zhou2, Dimitrios Tzachanis2, Tiffany Tanaka3, Asad Bashey4, Rafael Bejar3, Thomas Lane1,Edward D. Ball2, Antonella Vitiello1*
1PersImmune, San Diego, CA, 2Blood and Marrow Transplant Division and 3Hematology and Oncology Division, UCSD, San Diego, CA; 4Northside Blood and Marrow Transplant Division, Atlanta, GA
The 5-year survival rate for patients with AML is ~25% and the 2-year survival rate for patients with high risk MDS who fail standard therapy is ~15%. At present, the only curative therapy for most high-risk AML and MDS patients is allogeneic hematopoietic stem cell transplant (allo-HSCT). We have developed a personalized adoptive T cell therapy predicated on the concept that cancer is caused by somatic mutations that generate potentially novel immunogenic proteins (neoantigens).
Our process comprises (i) whole-exome and transcriptome sequencing of AML/MDS patient neoplastic blasts and exome and transcriptome sequencing of patient normal hematopoietic cells to identify non-synonymous tumor-unique DNA mutations; (ii) in silico screening of peptides spanning the resulting mutation to identify potentially immunogenic MHC-binding peptides; (iii) in vitro immunogenicity screening of candidate peptides against T cells from the AML allo-HSCT donor or the MDS patient; and (iv) selection of immunogenic peptides and large-scale generation of T cell lines with the desired neoantigen specificity and cytolytic activity for infusion into patients.
Here, we present data demonstrating the entire process of T cell generation, starting with identification of somatic mutations from AML/MDS patients through to in vitro generation of autologous and HLA-matched allogeneic cytotoxic T cell lines specific for neoantigen-expressing AML blasts.
Two phase I clinical trials to assess the safety and tolerability of this personalized T cell therapy in AML and MDS patients are planned for 2017.
Funded by Raffaella and John Belanich.
Credits: None available.
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