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Decoding response and toxicity to immune checkpoint inhibitors in lung cancer patients by noninvasive assessment of tumor microenvironment dynamics and circulating T cells

Award Number: R01CA317358
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Decoding response and toxicity to immune checkpoint inhibitors in lung cancer patients by noninvasive assessment of tumor microenvironment dynamics and circulating T cells - PROJECT SUMMARY Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the United States, killing ~125k people per year, with immunotherapy (IO) alone or in combination with chemotherapy being a cornerstone of treatment for both metastatic and locally advanced disease. Still, less than half of patients respond to IO-based treatment and ~20% develop severe immune-related adverse events (irAEs), most commonly life-threatening pneumonitis. Existing response biomarkers, such as tumor PD-L1 and tumor mutational burden (TMB) are suboptimal at predicting durable response or survival outcomes, and there is no clinical assay available to predict severe irAE, making personalization of IO challenging for this deadly cancer type. Our preliminary data suggest that multicellular programs within the tumor microenvironment (TME)—captured as spatial ecotypes (SEs)—are strongly associated with immunotherapy response and survival, and can be noninvasively quantified from blood plasma. We also have preliminary data showing that clonally diverse activated CD4 memory T cells are elevated in immunotherapy patients that develop severe toxicity. Based on these findings, we hypothesize that spatial TME ecosystems and CD4 T cell states are key determinants of IO-based response and toxicity in NSCLC, and that both can be measured using a liquid biopsy approach. To test this, we will analyze plasma and tumor tissue from 300 patients across three institutions (Mayo Clinic, MD Anderson Cancer Center, Princess Margaret Hospital)—200 with metastatic NSCLC and 100 with locally advanced resectable NSCLC in the neoadjuvant setting. We will determine whether liquid biopsy–derived ecotype profiles (“liquid ecotypes”) outperform conventional biomarkers such as tumor mutational burden (TMB), PD-L1 and circulating tumor DNA (ctDNA) in predicting response to IO-based therapy in patients with metastatic NSCLC (Aim 1) and in identifying ultra-responders with pathologic complete response in locally advanced resectable NSCLC (Aim 2). We will also assess whether CD4 T cell states in peripheral blood forecast severe irAEs (Aim 3). Overall, this study will establish a novel ecotype-based liquid biopsy platform for pre-treatment risk stratification and on- treatment dynamic monitoring in lung cancer patients receiving IO-based therapy. Moreover, our findings will lay the foundation for future precision oncology trials that personalize IO based on forecasted benefit and toxicity, in both metastatic and locally advanced settings.


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: 2026 ( Subtotal = $669,587 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cancer Treatment Research	000	1	9/10/2026	NEW	$669,587
														Subtotal = $669,587

Grand Total All Awards = $669,587

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Decoding response and toxicity to immune checkpoint inhibitors in lung cancer patients by noninvasive assessment of tumor microenvironment dynamics and circulating T cells

Award Number: R01CA317358

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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