Collaborating Investigator: Tim Chan, MD PhD
Affiliation: Cleveland Clinic
Director, Lerner Research Institute, Cleveland Clinic 

Funding Source: NIH
Grant Number: R35CA232097   
Project Period: 5/01/20-08/31/25

Significance

Immune checkpoint inhibitors have revolutionized the treatment of cancers. Both anti-CTLA4 and anti-PD-1 antibodies are now part of standard of care for certain cancers. However, the molecular determinants of response are still being defined and they remains one of the most important unanswered questions in oncology. The focus of the Chan laboratory is to understand the genomic basis of tumor development and treatment response. They use both large-scale genomic analyses and functional dissection to determine what drives oncogenesis. Using that information, they seek to develop improved diagnostic and therapeutic modalities for human cancers. 

Approach

Aim 1: Define the neoantigen landscape and anti-tumor T cell response that predict efficacy of immune checkpoint blockade therapy by neoantigen similarity with foreign antigen. Using whole exome sequencing, we identified and validated neoantigen responses homologous to pathogen B. pertussis in a non-small cell lung cancer patient who respond to anti-PD1 treatment and also have both HLA A11 and HLA B07-specific responses. We will create a HLA A11-HERC1 and B07- nano-aAPC and MP-based aAPC for expansion studies and cross reactivity to B. pertussis from patient blood after treatment.

Aim 2: Using a model neoepitope antigen Kb-SIY in murine melanoma model B16-SIY and Kb-SIY TCR redundancy with B. fido, we will measure Kb-SIY anti-tumor response and repertoire changes in Kb-SIY aAPC expanded cells in the presence or absence of B. fido exposure. Our preliminary data shows that E+E stimulates T cells using either Kb-SIY or Kb-SVY nano-aAPC and that these T cells are cross-reactive.  This confirms that there is clear overlap between the two responses which was reported on in our shared collaborative publication.  

We will further elucidate the affinity response for the cross-reactivity and the clonal diversity of Kb-SIY with and without pathogen influence in both naïve repertoire and after tumor exposure. We propose that this could serve as a model antigen to illustrate the mechanism of action of pathogen-neoantigen homology on anti-tumor response resistance. 

Push-Pull relationship

The Chan lab will alter the microbiome of specific B6 mice, from Jax and Taconic, and the NCBIB will send the Chan lab various formulations of nano-aAPC  and/or hydrogel-MP to test expansion for tumor-SIY and SVY-specific T cells. We will also provide HLA A11-based aAPC for studying cross-reactive neoepitope-specific T cells from lung cancer patient samples. Pull: Depending on the results, the NCBIB will formulate aAPC and/or hydrogel-MP with additional signal 2s or combinations of signal 2s that further facilitate microbiome differences in tumor-specific T cells.  We, TR&D1, will also generate additional HLA A and B-based aAPC to identify potential human cross-reactive T cells. While CP#1 is primarily associated with TR&D1, we may find that immunocytokines may be helpful as well in which case TR&D3 will also collaborate with CP#1.