Monday, June 23, 2025 6/23/2025

Immune Therapy for Brain Metastasis

Award Number: R01CA269286
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/18/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

Group Awards By:

View Award Description

Immune Therapy for Brain Metastasis - Melanoma is the solid tumor that metastasizes most frequently to the central nervous system (CNS). While major progress has been made in treating metastatic melanoma, advances in treating melanoma brain metastases (MBM) lag behind. This is due to near-universal exclusion of patients with untreated brain metastases from clinical trials, and only once a regimen is well established in extra-cerebral disease, is it studied in MBM patients. Moreover, pre-clinical studies of MBM have been hampered by a paucity of pre-clinical models and limited access to CNS specimens for analysis, as these patients are typically treated with radiation rather than surgery. We therefore developed infrastructure and resources which we propose to employ to better understand molecular, vascular and cellular underpinnings of brain metastasis. We started by studying activity of the PD-1 inhibitor pembrolizumab (pembro) in patients with untreated MBM on a phase II trial. Although the response rate was modest (26%), the two-year survival was 48%, and the incidence of radiation necrosis and/or neurologic symptoms related to edema was high. We therefore initiated a sequel trial of pembro plus bevacizumab in MBM; the response rate in the initial cohort was 55%, exceeding our expectations and warranting further evaluation. This response rate is similar to that seen with nivolumab and ipilimumab in MBM, but the toxicity profile is far superior with only minimal added toxicity from the bevacizumab. We propose to further study co-targeting the PD-1 and VEGF/VEGF-R pathways in MBM, and to determine the mechanism by which these pathways crosstalk to promote tumor growth within the brain. We will build on our success with anti-VEGF in a new trial involving pembro and a VEGF-R inhibitor (VEGFRi), lenvatinib. In parallel to our clinical research endeavors we developed novel immune-competent models of MBM that are modestly responsive to anti-PD-1, and developed in vitro models of the blood-brain-barrier to study effects of these drugs on vascular leak. These pre-clinical models will be used to test the hypothesis that the addition of VEGF pathway blockade to anti-PD-1 enhances T cell migration and function and directly decreases tight junction leakiness. We also hypothesize that anti-VEGF has different effects to VEGFRis. We will dissect the mechanism by which this occurs using our novel immune competent murine models and single cell transcriptomic and in situ proteomic strategies (Aim 1) and determine whether VEGF inhibiting drugs should be replaced with VEGF-Ris to treat MBM. We are expanding our ongoing clinical trial of pembro and bevacizumab by enrolling a second cohort of melanoma patients to verify our initial result. We have initiated a new trial of pembro and lenvatinib. We will analyze tumors and blood samples from patients on these trials in an attempt to validate mechanistic results from the murine experiments and identify predictors of response or resistance to this regimen (Aim 2). This proposal is responsive to PAR 21-033, which involves early phase clinical trials and biomarker and mechanistic studies. These studies can have important implications for other disease as well, such as lung cancer, which similarly metastasizes frequently to the CNS.


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 = $501,954 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	3	3/14/2025	NON-COMPETING CONTINUATION	$501,954
														Subtotal = $501,954

Issue Date FY: 2024 ( Subtotal = $542,905 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	001	2	4/24/2024	NON-COMPETING CONTINUATION	$28,573
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	2	3/20/2024	NON-COMPETING CONTINUATION	$514,332
														Subtotal = $542,905

Issue Date FY: 2023 ( Subtotal = $583,091 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Treatment Research	000	1	4/18/2023	NEW	$583,091
														Subtotal = $583,091

Grand Total All Awards = $1,627,950

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Immune Therapy for Brain Metastasis

Award Number: R01CA269286

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/18/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer