# Programming Durable Immune Responses in Lung Cancer

> **NIH VA I01** · VA GREATER LOS ANGELES HEALTHCARE SYSTEM · 2020 · —

## Abstract

We propose to evaluate the cellular and molecular mechanisms of immune responses following
stimulation with therapeutic vaccination and immune checkpoint blockade to establish effective immune
responses in lung cancer. We will target the programmed cell death protein 1 (PD-1) pathway that has
shown benefit in patients with lung cancer. Patients do not benefit from PD-1 blockade therapy if they
lack lymphocytic infiltration of the tumors. We have a novel means to cause tumor T cell infiltration with
CCL21 chemokine to make the PD-1 pathway therapy even more effective. To induce enhanced T cell
infiltration in the tumors, we will administer CCL21 gene modified dendritic cells (DC-AdCCL21) pulsed
with autologous tumor antigens. We have found that although administration of tumor antigen pulsed
DC-CCL21 inhibits tumor growth, PD-1 expression is upregulated on T cells in the TME. We anticipate
that this limitation can be overcome by PD-1 blockade combined with therapeutic vaccination. We have
found that IFNγ and TNFα are induced specifically in the tumor and systemically following therapy.
[The IFNγ induced chemokines CXCL9 and CXCL10 are induced in the tumor following therapeutic
vaccination]. Our central hypothesis is that the CCL21 based therapeutic vaccination will
augment immune recognition in lung cancer and modulate PD-1 immune checkpoint blockade
therapy. [We hypothesize that CXCL9 or CXCL10 induced in the TME following therapeutic
vaccination will recruit activated T cell infiltrates in the tumor]. We hypothesize that the individual
or combined therapy will enhance DC maturation and functional activity]. We hypothesize that that
the CTL activities following combined therapy will be greater than the therapies administered
individually. Utilizing preclinical murine lung cancer models, we will address the following aims. Aim
1A will determine the therapeutic value of anti-PD-1 and tumor antigen (lysate or peptide) pulsed DC-
CCL21 vaccination on the modulation of anti-tumor immune efficacy in vivo. [Aim 1B will determine
the role CXCL9 or CXCL10 on CTL infiltration in the tumors following therapeutic vaccination or
combined therapy]. Aim 2 will determine the effects of [individual or combined therapy] on DC
maturation, DC functional activity in the TME and systemically. These aims are innovative and have not
been addressed previously. These aims will improve our understanding of combined therapeutic
vaccination and PD-1 blockade in lung cancer and aid in the development of ef fective treatment options
for this disease. As a measure of anti-tumor efficacy in both aims, tumor burden, survival and changes
in the frequency and functional activities of immune effectors [T (CD4, CD8), NK, NKT and DC] and
immune suppressors [tumor associated macrophage (TAM), myeloid suppressor cells (MDSC) and T
regulatory (Treg)] will be quantified.

## Key facts

- **NIH application ID:** 9815459
- **Project number:** 5I01BX003171-04
- **Recipient organization:** VA GREATER LOS ANGELES HEALTHCARE SYSTEM
- **Principal Investigator:** SHERVEN SHARMA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815459

## Citation

> US National Institutes of Health, RePORTER application 9815459, Programming Durable Immune Responses in Lung Cancer (5I01BX003171-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815459. Licensed CC0.

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