Collaborating Investigator: David Avigan and Juan Varela
Affiliation: Deputy Associate Director, Clinical Science, Executive Committee; Beth Israel- Deaconess Medical Center

Funding Source: NIH
Grant Number: R01CA262629  
Project Period: 07/01/21 –06/30/26 

Significance

Drs. Avigan and Varela’s research interests lie in the field of tumor immunotherapy and its incorporation into bone marrow transplantation. David Avigan developed dendritic cell-tumor fusions to be used as tumor vaccines for clinical trial for patients with AML. They are also investigating novel approaches to allogeneic transplantation, including the use of non-myeloablative approaches. The group’s interest in the development of a dendritic cell-tumor fusion vaccine platform in the setting of acute myeloid leukemia (AML), a liquid tumor, serves as the basis of this new CP. While they have documented clinical responses and found evidence for T cell stimulations, they have not been able to mechanistically identify the antigen-specific responses to either shared AML tumor antigens or neoantigens.  

In addition they Avigan lab also has a mouse model of DC/mouse myeloma cell line that is used as experimental therapy model. In murine model they also see responses but have not fully defined the antigens. 

Approach

Aim 1: Define the CD8+ neoantigen in the dendritic cell-tumor fusion vaccine. While the Avigan group has sown efficacy of their DC-Tumor cell vaccine the specific antigens being presented and recognized have not been determined. A second aspect of the CP will be to study shared tumor antigen-specific T cells in the setting of AML, a liquid tumor that could have unique signal 2 requirements

Aim 2: Adaption of MP-based aAPC to an in vivo model for treatment of mouse myeloma. Studies will be performed to see if MP-based aAPC will augment the in vivo activity of the DC/mouse myeloma cell line model. Based on the results, MP-based aAPC can be modified to optimize their effects in this model.

Push-Pull relationship

Push: We will push unloaded HLA A2-based aAPC to the BIDMC group, where Varela, an expert on aAPC use, will determine the antigens stimulating the T cell responses to their dendritic cell-tumor fusion vaccine platform. In addition, they will strip peptides from their dendritic cell vaccine, load them on to the aAPC, and stimulate T cells from patients who have received the vaccine. A second aspect of the CP will be to study shared tumor antigen-specific T cells in the setting of AML, a liquid tumor that could have unique signal 2 requirements.

Pull: As a resource, we will optimize aAPC platforms, allowing them to load poorly defined peptides into the HLA A2-based aAPC. We will also provide various signal 2-based aAPC for expansion of common tumor antigen–specific CD4+ and CD8+ T cells in the context of the AML vaccine platform.