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HLA B44 motif neoepitopes in NSCLC: Evaluating their effects on the TME and adding them to established markers in a model to predict durable benefit from PD- 1 inhibition with and without chemotherapy

Award Number: R01CA276917
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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HLA B44 motif neoepitopes in NSCLC: Evaluating their effects on the TME and adding them to established markers in a model to predict durable benefit from PD- 1 inhibition with and without chemotherapy - PROJECT SUMMARY Lung cancer is the leading cause of cancer related deaths in the United States and the World. We recently demonstrated that programmed cell death 1 (PD-1) inhibitors, which lead to durable responses in a minority of non-small cell lung cancer (NSCLC) patients, have greater efficacy in patients with charged HLA-B binding pockets whose tumors harbor mutation(s) leading to what we have designated as motif neoepitopes. Motif neoepitopes have an amino acid substitution in the second position of a nonamer generating a change in charge from the wild type peptide with the resultant amino acid having a charge opposite from the HLA-B binding pocket. To date, the immunological changes induced by motif neoepitopes have not been explored. We propose a comprehensive evaluation of the underlying mechanism, focusing on patients with HLA-B44 supertype alleles because of the prevalence (approximately 40% of the population) and distribution of HLA-B44 across racial and ethnic groups. We will evaluate HLA-B44 samples in the cancer genome atlas (TCGA) to explore differences in the tumor microenvironment (TME) among patients with or without motif neoepitopes by examining gene expression and cellular composition by slide review and algorithms based on gene expression profiles. We will evaluate surgical specimens from treatment naïve patients with or without HLA-B44 motif neoepitopes and evaluate spatial signatures of the TME by multiplex immunofluorescence (MIF). We will assess multiple sections from each specimen to identify biomarkers most significantly associated with motif neoepitopes. We will further examine immune contextures of the TME associated with motif neoepitopes by single cell RNA-seq analysis. To elucidate the predictive value of motif neoepitopes in early and advanced stage NSCLC patients and to assess relevant clinical questions, we will perform analyses of patients in three separate clinical scenarios. As whole exome sequencing (WES) and transcriptomic data is now routinely obtained in our NSCLC patients as part of patients’ clinical care, we will analyze the presence and expression of genes harboring motif neoepitopes. We will evaluate baseline tumor biopsies from 75 early stage patients with an HLA-B44 allele who receive neoadjuvant chemotherapy plus PD-1 inhibition, correlating motif neoepitopes with pathologic complete response. Among 75 advanced stage patients with an HLA-B44 allele who are receiving single agent PD-1 inhibition and 75 additional patients being treated with chemotherapy plus PD-1 inhibition, we will correlate motif neoepitopes with progression of disease within 6 months of initiation of therapy. Together, these studies will provide a better understanding of the TME and other immunologic changes associated with the presence of motif neoepitopes. In addition, results could enable us to identify patients in whom evaluation of this marker of neoantigen presentation could be utilized to select patients with clinically relevant benefit in three separate clinical scenarios utilizing PD-1 inhibitor-based therapy. As a corollary, results could also identify populations of patients in whom other treatment strategies should be considered.


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 = $623,462 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	4	7/31/2026	NON-COMPETING CONTINUATION	$623,462
														Subtotal = $623,462

Issue Date FY: 2025 ( Subtotal = $848,595 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	3	9/4/2025	SUPPLEMENT FOR EXPANSION	$225,068
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	3	9/3/2025	NON-COMPETING CONTINUATION	$623,527
														Subtotal = $848,595

Issue Date FY: 2024 ( Subtotal = $817,420 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	001	2	8/6/2024	SUPPLEMENT FOR EXPANSION	$225,068
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	2	8/2/2024	NON-COMPETING CONTINUATION	$592,352
														Subtotal = $817,420

Issue Date FY: 2023 ( Subtotal = $620,831 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Detection and Diagnosis Research	000	1	7/26/2023	NEW	$620,831
														Subtotal = $620,831

Grand Total All Awards = $2,910,308

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HLA B44 motif neoepitopes in NSCLC: Evaluating their effects on the TME and adding them to established markers in a model to predict durable benefit from PD- 1 inhibition with and without chemotherapy

Award Number: R01CA276917

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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