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Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC

Award Number: R01CA247551
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC - Summary Despite recent advances in treatment, the overall mortality for head and neck squamous cell carcinoma (HNSCC) remains high and current treatment regimens incur significant long-term morbidity. Targeting the immune checkpoint PD-1 with pembrolizumab and nivolumab has revolutionized HNSCC treatment. However, the overall response rate of these immunotherapies remains low, around 15-20%. This highlights the urgent need to identify novel therapeutic options for HNSCC to improve mortality, reduce morbidity, and enhance the activity and response rate of immune oncology (IO) approaches for HNSCC. We hypothesize that targeting HNSCC oncogenic signaling networks and disabling their immune evasive mechanisms may increase the response to anti-PD-1 treatment as part of a novel rational therapeutic strategy. In this regard, our laboratory contributed to the discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that mTOR inhibition exerts potent antitumor activity in multiple experimental HNSCC model systems and in a Phase 2 clinical trial (NCT01195922). Remarkably, ~20% of HNSCC lesions harbor driver PIK3CA mutations encoding active PI3Kα subunits, and yet ~90% of HNSCC lesions exhibit aberrant PI3K/mTOR pathway signaling. In search for the underlying mechanisms, we conducted a kinome wide RNAi screen, which revealed that persistent HER3 tyrosine phosphorylation and association with PI3Kα sustain pathway activation in most of the HNSCC lesions. Indeed, HER3 is highly expressed and persistently activated in most HNSCC lesions, correlating with poor prognosis. The best-in-class anti-HER3 monoclonal antibody CDX-3379 inhibits the ligand-dependent and -independent activation of human and murine HER3 by locking HER3 in its auto-inhibited configuration, and has demonstrated pharmacodynamic and clinical activity in HNSCC patients. CDX-3379 exhibits potent antitumor activity in PIK3CA wild type HNSCC tumor xenografts and patient derived xenografts (PDXs). Furthermore, we have obtained strong preliminary results supporting that CDX-3379 administration 1) abolishes PI3K-mTOR signaling, 2) reverses the immune evasive HNSCC microenvironment, and 3) can result in complete remission when combined with anti-PD-1 therapies in recently developed syngeneic mouse HNSCC models. Our premise is that co-targeting the HER3 signaling circuitry combined with anti-PD-1 blockade may represent a novel multimodal precision therapeutic approach for HNSCC aimed at achieving durable responses and cancer remission. We will now aim 1) to elucidate the contribution of genomic alterations in the PI3K-mTOR signaling network to anti-HER3 sensitivity and resistance, and 2) to establish the impact of targeting and co-targeting the HER3-PI3K/mTOR signaling network on the tumor immune microenvironment and response to PD-1 blockade, aiming at achieving a single cell level understanding of the anti-cancer immune response. These studies will inform the molecular stratification for patient selection in future multimodal precision immune oncology 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	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	5	4/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $474,976 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$25,001
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	5	11/30/2023	NON-COMPETING CONTINUATION	$449,975
														Subtotal = $474,976

Issue Date FY: 2023 ( Subtotal = $489,974 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	002	4	6/20/2023	NON-COMPETING CONTINUATION	$0
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	4	3/20/2023	NON-COMPETING CONTINUATION	$39,999
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	4	11/16/2022	NON-COMPETING CONTINUATION	$449,975
														Subtotal = $489,974

Issue Date FY: 2022 ( Subtotal = $489,974 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	3	6/23/2022	NON-COMPETING CONTINUATION	$39,999
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	3	12/7/2021	NON-COMPETING CONTINUATION	$449,975
														Subtotal = $489,974

Issue Date FY: 2021 ( Subtotal = $499,263 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	2	11/17/2020	NON-COMPETING CONTINUATION	$474,301
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	2	1/28/2021	NON-COMPETING CONTINUATION	$24,962
														Subtotal = $499,263

Issue Date FY: 2020 ( Subtotal = $513,131 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	1	11/22/2019	NEW	$501,109
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	1	1/23/2020	NEW	$12,022
														Subtotal = $513,131

Grand Total All Awards = $2,467,318

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Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC

Award Number: R01CA247551

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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