Abstract 5101: CAB-CAR-T: The prioritization of cell surface protein targets for conditionally active biologics to treat all solid tumors
Authors: Shaban Hiba A. , Jadin Laurence , Onuffer James , Haerizadeh Farzad , Kerner Alissa , Schreiber Gregory , Frost Gregory , Willis Scooter 
Published: August 2019

Introduction

Proteins on the surface of cancer cells represent viable targets for conditionally active biologic (CAB) CAR-T therapy that only work in the tumor microenvironment. By modeling properties of cell surface proteins from TCGA datasets we seek to identify optimal targets across all TCGA cancer cohorts that when used in CAB-CAR-T therapies will provide the greatest number of treatment options for patients across all cancer malignancies.

Method

Cell surface proteins(n=1086) were identified and meta data specific to each gene was organized from a variety of public databases for data modeling. Various approaches based on ideal CAB-CAR-T properties are used to rank the cell surface proteins as therapeutic targets. The 31 TCGA cohorts representing the most comprehensive collection of genomic profiled tumor samples and outcomes of all cancers is used to rank cell surface proteins for the percentage of patients in each cohort who would be eligible for treatment based on predetermined mRNA cutoffs.

Various approaches were used to filter the ranked list based on ideal CAB-CAR-T properties: known antibodies that can be used for initial CAB-CAR-T development, non-receptor as a static protein structure, highly expressed in CCLE indicating mRNA expression is a feature of cancer cell lines and low expression in critical tissues like Heart, Lung, Liver, Muscle etc. Different ranked lists of cell surface proteins were used to determine the number of CAB-CAR-T products required to treat 90% of patients in TCGA cohorts. A patient with the highest mRNA expression above the mean plus one standard deviation as determine across all TCGA samples is assigned to that specific protein biomarker as eligible for treatment and removed from the list of patients still to be treated. A bootstrap p-value for the ranked lists was determined by calculating the minimum number of randomly selected cell surface proteins that would give 90% coverage of the TCGA cohort.

Results

It was shown that it is reasonable to find ranked list of genes with high mRNA expression in TCGA and minimum expression in off-target critical tissue that 5-7 CAB-CAR-T products could be used to treat 90% of TCGA patients. To achieve 100% treatment coverage each additional CAB-CAR-T product added to the list had minimum inclusion of additional patients for treatment.

Conclusions

By modeling various properties of cell surface proteins to establish future development of CAB-CAR-T products it is reasonable to expect 90% patient coverage with 10 distinct therapies. Further modeling will be performed to exam combination therapies where tumor heterogeneity is an important criteria for the ranked list to have efficacy, with a goal of maximizing complete responses (CRs) and minimize the chance of relapse in the future.

Citation Format: Hiba A. Shaban, Laurence Jadin, James Onuffer, Farzad Haerizadeh, Alissa Kerner, Gregory Schreiber, Gregory Frost, Scooter Willis. CAB-CAR-T: The prioritization of cell surface protein targets for conditionally active biologics to treat all solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5101.