Abstract B137: Establishment of a variety of primary mouse tumor allografts of defined disease pathways for evaluating immunotherapy

Abstract

Abstract Lack of relevant animal model is a major bottleneck for developing novel immunotherapy. The current workhorse is syngeneic mouse tumor model where mouse cancer cell lines were engrafted in syngeneic mice. However, these models suffer from several limitations: 1) only a few available and responsive to the current checkpoint inhibitors – for given strains of mouse, few choices of cells/disease types; 2) not mimicking patient tumors since it is in vitro immortalized cell lines1; 3) not reflective of patient disease pathways thus unfit for common target agents, either in mono- or combination therapy. We have attempted to establish allografts of spontaneous mouse tumors derived from GEMMs (MuPrime®) as a new type of immuno-oncology models2 with following advantages: 1) its primary nature of “stem cell diseases” and relevant tumor microenvironment as seen in patient derived xenografts (PDX) or patients1; 2) its diverse cancer types/strains of mice; 3) engineered oncogenic drivers as seen in human diseases, e.g. heterozygous APCmin/wt3,4,5, deriving from a wide range of available GEMMs, suitable for targeted agents. Thus far, we have continued to build a small library of allografts and are testing them to facilitate pharmacological investigation, particularly those of immuno-oncology. Kras G12D mutation and p53 loss-of-function are most common genetic abnormality found in a variety of cancers, e.g. lung, pancreas, colon, lymphoma, etc. We generated a conditional compound mutant GEMM. By introducing adeno-Cre to different organ sites of this GEMM, we created a series of mouse tumors, including lung, pancreas, colon, and lymphoma, with genetic lesions of KrasG12D/+/P53(-/-). We have further allografted subcutaneous these tumors into syngeneic parental mous strain. These allograft tumors, while carrying same mutations, display distinct histopathology: pancreatic tumor exhibits the features commonly found in human PDAC (e.g. glandular tumor structures and exuberant stroma); lung cancer features NSCLC-adenocarcinoma. They also demonstrated different tumor immune microenvironment. This set of allografts of different diseases but of the same oncogenic driver could be particularly ideal to investigate their sensitivities to immunotherapies, as well as to combination therapies targeting MAPK pathway and immune modulation. At present, we are genomically, immunologically and pharmacologically profiling these models. The data of these studies will be presented at the meeting.