Thursday, November 21, 2024 11/21/2024

Dissecting neoepitope-specific clonal T cell populations in advanced melanoma patients vaccinated with personal neoantigen peptides partnered with local and systemic immune checkpoint Inhibition

Award Number: R01CA229261
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By:

View Award Abstract

Project Summary Our long-term goal is to provide melanoma patients with therapies that produce safe, effective, and durable tumor control. Immune checkpoint blockade (ICB) with anti-PD-1 and anti-CTLA-4 antibodies is approved for the treatment of melanoma, however a large subset of patients has primary or secondary resistance to these agents. Cancer Vaccines provide an opportunity to generate new and amplify existing antigen-specific T cell responses focusing the immune response against tumor cells and potentially synergizing with immune checkpoint blockade. Neoantigens are a promising novel class of cancer vaccine targets created by the personal mutations found in each patient's tumor because they are exquisitely specific to the tumor and not subject to central tolerance. Recently, in patients with high-risk melanoma, we demonstrated proof-of-concept of the safety, feasibility, and immunogenicity of a personal neoantigen vaccine utilizing synthetic long peptides and the TLR3 agonist poly-ICLC (called NeoVax). We now propose a phase 1 clinical trial in patients with advanced melanoma that seeks to enhance the efficacy of NeoVax at 3 critical nodes of the tumor immune response by i) admixing NeoVax with the mineral oil-based immune adjuvant Montanide (improved formulation), ii) administering the anti-CTLA-4 antibody Ipilimumab adjacent to the vaccine injection site (enhanced priming), and iii) partnering the vaccine with the PD-1 directed antibody Nivolumab (re-invigorating T-cells infiltrating the tumor). We propose innovative immunological analyses to understand the activity of the modified vaccine and Nivolumab utilizing serially collected blood and tumor biopsies. In addition to standard bulk profiling of T cells, we will characterize T cell receptor (TCR) repertoires by sequencing T cell receptors in single peripheral and tumor infiltrating T cells for clone-paired TCRα and TCRβ chains, and screening of paired TCRs against vaccine epitopes to identify cognate neoantigens of each TCR. Finally, we will use single cell RNA-sequencing of the same tumor infiltrating T cells to determine their activation state and determine if tumor-reactive T cells adopt unique states, and to monitor changes in activation before and after therapy. Our studies will help identify the critical neoantigens, T cell receptors, T cell activation states and immune subpopulations that underlie immunity against tumors in the clinical trial. We will thus determine the impact of Nivolumab relative to neoantigen vaccination on the induction of anti-tumor T cells, determine the immunogenicity of the selected neoantigens and provide insights for improving the design and analysis of future neoantigen vaccine trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	5	11/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $615,390 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	5	8/10/2023	NON-COMPETING CONTINUATION	$615,390
														Subtotal = $615,390

Issue Date FY: 2022 ( Subtotal = $627,949 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	4	8/23/2022	NON-COMPETING CONTINUATION	$627,949
														Subtotal = $627,949

Issue Date FY: 2021 ( Subtotal = $627,949 )
2021	2021	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	3	8/24/2021	NON-COMPETING CONTINUATION	$627,949
														Subtotal = $627,949

Issue Date FY: 2020 ( Subtotal = $627,949 )
2020	2020	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	2	8/6/2020	NON-COMPETING CONTINUATION	$627,949
														Subtotal = $627,949

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	1	8/21/2019	NEW	$0
2019	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	002	1	9/2/2019	NEW	$0
2019	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	11/15/2018	NEW	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $627,949 )
2018	2018	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	1	9/6/2018	NEW	$627,949
														Subtotal = $627,949

Grand Total All Awards = $3,127,186

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Dissecting neoepitope-specific clonal T cell populations in advanced melanoma patients vaccinated with personal neoantigen peptides partnered with local and systemic immune checkpoint Inhibition

Award Number: R01CA229261

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer