# Optimizing Cancer Immunotherapy Safety and Efficacy using Genome Editing

> **NIH NIH R00** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $248,999

## Abstract

The adoptive transfer of lymphocytes engineered to recognize tumor cells has shown tremendous promise in
patients with relapsed or refractory B cell malignancies. In this approach, patient derived T cells are programmed
in vitro with engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs) that have affinity for cancer-
or lineage-specific antigens. Subsequent autologous reinfusion of the engineered T cells enables tumor targeting
and eradication. More recently, genome editing approaches have been proposed to improve engineered T cell
performance by knocking out genes that mediate graft-versus-host disease (for allogeneic transfer), that are
involved in tumor-mediated suppression of T cell efficacy, or that are recognized by potent clinically relevant
monoclonal antibodies. However, to this point no robust characterization of genome editing efficiency or
specificity has been performed in T cells. Much of my postdoctoral work has focused on developing methods to
characterize and improve the utility and genome-wide specificity of CRISPR-Cas nucleases, making me uniquely
suited to address this largely outstanding question. The primary aims of this proposal are therefore: 1) to
characterize and optimize the efficiency and specificity of genome editing in T cells, 2) utilize genome editing to
improve processes involved in T cell engineering, and 3) leverage CRISPR-Cas screens to enhance the overall
efficacy of engineered T cells. The proposed research will provide considerable insight into the feasibility of
implementing genome editing strategies in T cells as a means to improve tumor killing efficacy, persistence, or
manufacturing. Significant findings relevant to the fields of cancer immunotherapy, cancer biology, genome
editing, and gene therapy are expected. Areas of additional scientific training that will enable successful
completion of this proposal are knowledge of T cell biology and immunology, mentorship on in vivo cancer
modeling in mice, and experience implementing genome-wide CRISPR-Cas screens. The mentored phase of
the award will be supported by Dr. Keith Joung, a world-leader in genome editing technology development, and
by Dr. Marcela Maus, an expert in cancer immunotherapy. Dr. Joung, Dr. Maus, and nearly all other senior/key
personnel of this project are located at the Massachusetts General Hospital or in the greater Boston scientific
community. Professional and career development activities will include training in mentorship, responsible
conduct of research, grantsmanship, finance, and conflict of interest among other topics. National and
international meetings will continue to be attended to disseminate findings from the proposed research. The
academic and professional development environment at the Massachusetts General Hospital and Harvard
Medical School, combined with a top level mentorship team and scientific advisory committee, will offer the best
opportunity for further training as I transition to independenc...

## Key facts

- **NIH application ID:** 9980799
- **Project number:** 5R00CA218870-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Benjamin Peter Kleinstiver
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980799

## Citation

> US National Institutes of Health, RePORTER application 9980799, Optimizing Cancer Immunotherapy Safety and Efficacy using Genome Editing (5R00CA218870-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9980799. Licensed CC0.

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