# Resistance To Targeted Immunotherapies:CART19 as a Paradigm

> **NIH NIH R00** · UNIVERSITY OF PENNSYLVANIA · 2020 · $248,999

## Abstract

PROJECT SUMMARY/ABSTRACT
Chimeric-antigen receptor (CAR) T cells have opened a new era for targeted immunotherapy of cancer. The
applicant's mentor, Dr. Carl June, is recognized as a world leader in the field of genetically-engineered T cell
therapy for hematologic malignancy. Although anti-CD19 CAR T cells (CART19) generate unprecedented
responses in patients with B-cell leukemia and lymphoma, relapse represents the major cause of treatment
failure. The long term goal of this proposal is to develop an independent research career focused on improving
targeted immunotherapy by studying and neutralizing tumor evasion mechanisms. The unifying objective of
this application is to design novel strategies for the treatment and prevention of tumor immunoescape based
on the mechanisms leading to relapse, using CART19 as a model. The central hypothesis is that multiple
mechanisms can lead to escape from immune attack; therefore, combined approaches targeting the problem
from multiple sides will prevent escape. The rationale for this research is that identification of key tumor escape
mechanisms would allow us to develop specific remedies for these. The central hypothesis of this proposal will
be tested by pursuing two specific aims: 1) to characterize the pathogenesis of leukemia relapses occurring
after CD19-targeted immunotherapies by studying minor CD19-negative resistant clones present before
CART19 treatment and by identifying key resistance pathways in CD19-positive relapses using functional
genomics; 2) To design dual-specific chimeric antigen receptor T cells that will prevent tumor escape. This
research will be significant because it will contribute depth (of understanding the mechanisms of relapse) and
breadth (of novel potentially curative therapy) to the immunotherapeutic arsenal against cancer. Ultimately,
such knowledge has the potential to vertically advance the field of CAR-redirected T cell immunotherapy as
well as other targeted immunotherapies. This is project is innovative because it combines high throughput
screening techniques together with in vitro and in vivo functional studies to study the possible mechanisms of
resistance after immunotherapy and therefore to generate novel treatments. The proposed research activities
are crucial to the development of the applicant as an independently-funded scientist with a focus on cellular
immunotherapy. Dr. Ruella will receive further training in molecular biology, translational medicine, and
immunology from his mentors and training in next-generation sequencing, cancer biology and bioinformatics
from experienced collaborators at the University of Pennsylvania. Therefore at the conclusion of the training
period, the applicant will have acquired a unique set of intellectual and technical skills that will allow him to
attack the problem of resistance to targeted immunotherapies from several angles at once. In addition, this
award will support a unique training experience in translational research...

## Key facts

- **NIH application ID:** 9959356
- **Project number:** 5R00CA212302-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marco Ruella
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $248,999
- **Award type:** 5
- **Project period:** 2018-09-12 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9959356

## Citation

> US National Institutes of Health, RePORTER application 9959356, Resistance To Targeted Immunotherapies:CART19 as a Paradigm (5R00CA212302-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9959356. Licensed CC0.

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