# Enhancing Cancer Immunotherapy: Targeting the Tumor and Targeting the Host

> **NIH NIH R35** · STANFORD UNIVERSITY · 2020 · $863,419

## Abstract

PROJECT SUMMARY/ABSTRACT
We can enhance antibody therapy by stimulating the action of natural killer (NK) cells by a single second
antibody. We can trigger a global therapeutic immune response by “in situ vaccination”, the injection of TLR
ligands directly into one tumor site. We are conducting clinical trials of both of these approaches and the early
results are very promising. The addition of antibodies that block immune checkpoints make these approaches
even more powerful. We will conduct preclinical and clinical projects based on these platforms.
1. Enhancing antibody therapy of cancer with a second antibody that stimulates activated NK cells. We
discovered that the therapeutic activity of Rituximab and other mAbs (Traztuzumab and Cetuximab) are
enhanced by the sequential addition of a second antibody against CD137 (41BB), an activation molecule on
the NK killer cells. We are now leading clinical trials that test the addition of CD137 antibodies to Rituximab in
patients with B cell lymphoma. Simultaneously, we are testing bispecific antibodies that bind both to the tumor
and to activation markers on NK cells.
2. Therapeutic In Situ Vaccination. We demonstrated that a global therapeutic anti-tumor immune response
can be triggered by the injection of TLR ligands into a single tumor site. We are conducting a phase I/II clinical
trial in lymphoma patients, testing the combination of low dose XRT followed by intra-tumoral injection of both a
TLR agonist and a low dose of anti CTLA4 antibody. We now have preclinical evidence for synergy between in
situ vaccination and Ibrutinib, an inhibitor of BTK and ITK, a combination that works also in solid tumors.
3. The Immune Response against immunoglobulin (Ig)-derived peptides in B cell lymphoma
B-cell lymphomas express a unique immunoglobulin idiotype that distinguishes malignant cells from normal B-
cells. Idiotypes are ideal targets for immunotherapy because they are expressed on all the malignant cells in
the patient. We discovered that patients have T cells that recognize peptides derived from idiotypes that are
displayed in MHC class II molecules. Now we will design new immunotherapy directed at MHC II-idiotypes.
4. New Methods of Immune Monitoring
A critical component of each of our immunotherapy projects is an intense focus on monitoring cells in the tumor
microenvironment. We will obtain samples from the same tumor sites: before, during, and after the
experimental therapies and analyze the cell populations by high-dimensional flow cytometry.
These data sets will be compared across trials that test different modalities of immunotherapy.
We will detect activated T cells in patients by novel non-invasive imaging techniques to track the effects of
immunotherapies in real time .We will detect the tumor-reactive cell populations in tissue sections by
Multiplexed Ion Beam Imaging (MIBI). This system can interrogate 10 or more parameters per cell with high
spatial resolution on sections from FFPE embedde...

## Key facts

- **NIH application ID:** 9999466
- **Project number:** 5R35CA197353-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** RONALD LEVY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $863,419
- **Award type:** 5
- **Project period:** 2016-09-02 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999466

## Citation

> US National Institutes of Health, RePORTER application 9999466, Enhancing Cancer Immunotherapy: Targeting the Tumor and Targeting the Host (5R35CA197353-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999466. Licensed CC0.

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