Universal platform for car therapy targeting a novel antigenic signature of cancer

Abstract

The present invention provides a method of identifying a target for preparing an inhibitory chimeric antigen receptor (iCAR) or a protective chimeric antigen receptor (pCAR) capable of preventing or attenuating undesired activation of an effector immune cell. Also provided are a list of iCAR targets, as well as vectors and transduced effector immune cells comprising the nucleic acid molecule and methods for treatment of cancer comprising administering the transduced effector immune cells are further provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims priority to U.S. Provisional Application No. 62 / 564,454, filed Sep. 28, 2017, and U.S. Provisional Application No. 62 / 649,429, filed Mar. 28, 2018, each of which is herein incorporated by reference.SEQUENCE LISTING[0002]This patent application contains a Sequence Listing which has been submitted electronically in ASCII format and are hereby incorporated herein by reference in its entirety. Said ASCII copy, created Sep. 27, 2018, is named 120575-5003_ST25.txt.ASCII TABLE[0003]The provisional patent application to which the current application claims priority contains a lengthy table section. A copy of the table was submitted to the U.S. Patent and Trademark Office on compact disc in ASCII format with priority U.S. Provisional Application No. 62 / 649,429, filed Mar. 28, 2018 and is hereby incorporated by reference, and may be employed in the practice of the invention. Said ASCII table, created Mar. 28, 2018, is as fol...

AI Technical Summary

Benefits of technology

This approach allows for precise targeting of tumor cells while sparing normal cells, potentially broadening the range of tumor antigens that can be safely targeted and reducing off-tumor reactivity, thereby enhancing the efficacy and safety of CAR T-cell therapy.

Problems solved by technology

The identification of targetable antigens that are exclusively expressed by tumor cells but not by healthy tissue is undoubtedly the major challenge in cancer immunotherapy today.

Yet, as stated in the title of a recent review by S. Rosenberg, “Finding suitable targets is the major obstacle to cancer gene therapy” (Rosenberg, 2014).

However, if activation and costimulation are split in the same T-cell between two CARs, each specific for a different antigen, then full blown response would require the cooperation of the two complementary signals that could only be accomplished in the presence of the two antigens.

Whether such balance can be routinely attained in the clinical setting is still questionable.

The approach of using iCARs to reduce on-target off-tumor reactivity suffers from a dire lack of antigens downregulated in tumor cells but present on normal tissue.

However, cumulative findings suggest that neoantigen-based T cell immunotherapies are more likely to be effective in cancers displaying higher mutational load, such as melanoma and lung cancers, but may often fail to show benefit in most cancers with fewer mutations (Savage, 2014; Schumacher and Schreiber, 2015).

Furthermore, considerable intratumoral heterogeneity (Burrell et al., 2013) entails the simultaneous co-targeting of several antigens so as to avoid emergence of mutation-loss variants, a task which becomes increasingly demanding in view of the scarcity of useful immunogenic neopeptides.

All in all, the urgent need to identify suitable targets for cancer immunotherapy via the adoptive transfer of genetically redirected killer cells is still largely unmet.

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