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Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers

Award Number: R01CA238217
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/06/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers - Abstract While immune checkpoint blockade (ICB) has emerged as a validated therapeutic axis in a variety of cancers, initial monotherapy strategies have proven beneficial only to a subset of patients. These studies have suggested the importance of T-cells in responsive cancers, thus strategies to improve T-cell stimulation and infiltration have been prioritized. However, our recent studies (Shuptrine et al., 2017) have identified the CD47/SIRPα innate pathway, which governs antibody dependent cell phagocytosis (ADCP), as one of the most critical potential mediators of anti-tumor immunity. This suggests that complementary innate anti-tumor effector pathways involving antibodies, particularly relating to ADCP, may represent critical pathways to establish effective anti-tumor responses. Recent positive results from the first clinical study using CD47 innate ICB (with CD20 mAb in resistant lymphoma) strongly suggest that this may be a clinically effective means to stimulate immunity in cancers (Advani, NEJM, 2018). This may be best explored in solid cancers in HER2+ Breast Cancer (BC), which are currently treated using HER2 mAbs that we recently determined function through ADCP (Tsao et al., JCI-Insight, in review). Additionally, we have also recently published positive responses from a vaccine strategy targeting HER2, documenting the induction of polyclonal antibodies (pAbs) in HER2+ BC patients (Crosby et al., CCR 2019). We have now identified these HER2 pAbs to elicit anti- tumor effects through the activation of complement, allowing our study of how pAbs (in contrast to monoclonal HER2-Abs) may differentially impact tumor immunity. Based on our recent adaptive ICB mechanistic studies, (Crosby et al., 2018), our central hypothesis is that HER2-targeted mAbs or pAbs elicit antibody dependent phagocytosis (ADCP) that is enhanced by CD47 blockade to immunologically to recruit and prime effector T- cells that can be expanded through the use of CTLA4 adaptive ICB mAbs and functionally enhanced by the use of PD1 ICB mAbs. Guided by our preliminary data, this hypothesis will be tested by utilizing our unique HER2+ BC models that can be interrogated with the following combinations that comprise our specific aims: 1) HER2+CD47 mAbs 2) HER2/CD47 mAbs + CTLA4/PD1 ICB combinations and 3) HER2 vaccination + innate CD47 ICB and CTLA4/PD1 adaptive ICB combinations. These studies will be the first to determine how these innate and adaptive ICB combinations impact Ab-mediated anti-tumor immunity and mechanistically alter tumor-specific and non-specific adaptive responses, as well as determine how the HER2 pAb activation of complement and direct T-cell stimulation can alter anti-tumor immunity in an endogenous HER2 immune- competent model that possesses few neoepitopes and is αPD1 resistant. The proposed research is significant, because if fundamental mechanisms and synergies are identified with minimal toxicities, these approaches could be utilized with targeted mAbs and vaccines in other solid cancers to expand and enhance the potential utility of immunotherapy as a therapeutic option for the majority of cancers.


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 = -$55,322 )
2025	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	5	4/7/2025	NON-COMPETING CONTINUATION	-$55,322
														Subtotal = -$55,322

Issue Date FY: 2024 ( Subtotal = $384,482 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$364,247
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$20,235
														Subtotal = $384,482

Issue Date FY: 2023 ( Subtotal = $516,840 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Treatment Research	000	4	1/31/2023	NON-COMPETING CONTINUATION	$516,840
														Subtotal = $516,840

Issue Date FY: 2022 ( Subtotal = $601,640 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	001	3	5/24/2022	NON-COMPETING CONTINUATION	$49,114
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	3	12/22/2021	NON-COMPETING CONTINUATION	$552,526
														Subtotal = $601,640

Issue Date FY: 2021 ( Subtotal = $490,346 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	001	2	1/21/2021	NON-COMPETING CONTINUATION	$20,237
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	002	2	9/3/2021	SUPPLEMENT FOR EXPANSION	$85,627
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	2	11/19/2020	NON-COMPETING CONTINUATION	$384,482
														Subtotal = $490,346

Issue Date FY: 2020 ( Subtotal = $414,073 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	000	1	12/6/2019	NEW	$404,096
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Cancer Treatment Research	001	1	1/22/2020	NEW	$9,977
														Subtotal = $414,073

Grand Total All Awards = $2,352,059

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Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers

Award Number: R01CA238217

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/06/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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