Vaccinex : Phase I Study of Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine and Pepinemab/Trastuzumab in Patients with Metastatic HER2-Positive Breast Cancer (MBC)

SITC 2022

Abstract 645

Phase I Study of Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine and Pepinemab/Trastuzumab in Patients with Metastatic HER2-Positive Breast Cancer (MBC)

Hyo S Han1, Elizabeth Evans2, Terrence Fisher2, Hatem Soliman1, Hung Khong1, Aixa Soyano1, Ricardo Costa1, Loretta Loftus1, Kimberly Lee1, Avan Armaghani1, Hien Liu1, Frederick Locke1, Alexandria Shrewsbury1, Jessica Malka1, Lavakumar Karyampudi1 , Maurice Zauderer2, Brian Czerniecki1

1 Moffitt Cancer Center, Tampa, FL

2 Vaccinex, Inc., Rochester, NY

PURPOSE / OBJECTIVE

BACKGROUND

CLINICAL TRIAL DESIGN

Despite major improvement of overall survival of HER2+ metastatic breast cancer (MBC) with effective HER2 targeted therapies, many patients experience significant toxicities and develop progressive disease during treatment. Therefore, new and more effective therapeutic options are needed. This novel approach will evaluate whether the combination of three immunotherapies in addition to trastuzumab: dendritic cell (DC) vaccination, anti-SEMA4D blocking antibody (pepinemab) and CD4+ T cell adoptive transfer can lead to improved outcomes for patients with MBC refractory to HER2-targeted agents.

BC have been considered as immunologically cold which is attributed to immune evasion and suppression of host effector immune cells homing into tumor bed. Progressive loss of Th1 immunity against HER2 oncodriver correlates with poor prognosis. HER2-peptide-pulsed type I dendritic cells (HER2-DC1) restored anti-HER2 CD4+ Th1 immune response and improved pathologic complete response (pCR) in HER2+ BC [1].

Antibodies to SEMA4D have been shown to modulate the TME by increasing effector cell infiltration and reducing immunosuppression [2,3]. In preclinical studies, treatment with anti-SEMA4D and HER2-DC1 in mice bearing established HER2+tumors improved DC homing, expansion of CD4+ T cells, and complete tumor regression, compared to treatment with anti- SEMA4D or HER2-DC1 alone. Further, subsequent expansion and adoptive transfer of CD4+ T cells induced synergistic anti-tumor activity by activating CD8+ T mediated cytotoxicity. Pepinemab was well-tolerated [4,5] and showed signs of anti-tumor activity in immunotherapy-resistant,PD-L1 negative/low non-small cell lung cancer patients when combined with checkpoint inhibitor (avelumab) [3].

HER2-peptide-pulsed type I dendritic cells (HER2-DC1)restored anti-HER2CD4+ Th1 immune response

and improved pathologic complete response (pCR) in HER2+ BC

Accumulation of T and B cells occurs in patients responding to

HER2-pulsed DC1 vaccines

SEMA4D is expressed in BC

HER2+ Breast	SEMA4D in
Cancer	cytokeratin positive
DCIS	8/15
IBC	7/13

SEMA4D+

Preclinical mouse HER2+ Breast Cancer Models - Combination therapies	SEMA4D MAb,	Treated	DC-1 vaccine,
Transplantable HER2+ TUBO model	systemic	intra-tumoral
tumor

Phase I, Investigator-sponsored Trial, open-label, dose escalation

*

*

Pepinemab 20mg/kg

MATERIALS & METHODS

This open label Phase 1 study is enrolling up to 28 patients with HER2+ MBC. Patients will be treated with 6 weekly injections of dendritic cell (DC1) vaccines in combination with trastuzumab and pepinemab. We hypothesize these therapies may elicit CD4+ HER2-specific T cell responses. HER2- specific T cells will be expanded ex vivo and subsequently infused to patients following lymphodepletion with cyclophosphamide. Trastuzumab and pepinemab will be given as maintenance in addition to booster DC1

Control SEMA4D Mab DC-1 vaccine

DC-1 + SEMA4D MAb

Untreated

distant tumor

SEMA4D antibody improves the balance of pro-

inflammatory M1 APC over suppressive M2 APC and MDSC

& promotes infiltration of lymphocytes

macrophageM1 (F4/80+IAd+CD80+)# tumor/mgthein	1.4×105	M1 Macrophage	macrophageM2 #(F4/80+CD206+) tumor/mgthein	4.2×105	M2 Macrophage	tumor/mgthein#MDSCs	3×105	MDSC
1.2×10	5	3.1×10	5	2.4×10	5
	1×105			2×105			1.8×105
	8×104			9×104
	6×104					1.2×105
	4×104			4.5×104			6×104
	2×104			0			0
	0

Patients with Metastatic

HER2+ Breast Cancer

Key Inclusion Criteria

• histologically confirmed HER2 positive breast cancer
• RECIST v1.1 measurable disease
• With disease progression while on trastuzumab for the treatment of HER2+ MBC.
• A maximum of 3 prior lines of cytotoxic chemotherapy in the setting of metastatic disease.
• ECOG performance status 0 or 1.

• Trastuzumab 8 mg/kg IV C1D1, then 6 mg/kg Q3W

DC1 vaccines 1-2x107 cells, intra-lesional, weekly

Autologous Expanded CD4+ T cells

Expanded CD4+ T cells dose escalation scheme

Cohort	N	IL-15 Expanded	IL-7 Expanded
		HER2-specific	HER2-specific
		CD4+ Th1 cells	CD4+ Th1 cells

Primary Endpoints

Safety/Tolerability -

• CTCAE (NCI Common Terminology Criteria Adverse Events) version 5.0
• Maximum Tolerated Dose (MTD) of expanded CD4+ T cells

Secondary Endpoints

• Efficacy: RECIST criteria version 1.1, clinical benefit

rate (CBR) at 6 months, and progression free

vaccines.

Patients (ECOG 0,1) must have had disease progression while on trastuzumab for the treatment of HER2+ MBC and received no more than 3 lines of therapy in the setting of metastatic disease. Dose escalation will

			4×104	CD8+ T cell		2×105	B cell
		cellsTCD8+# tumor/mgthein	3×10	4
				#cellsBCD19+ tumor/mgthein	1.5×105
		2×104
SEMA4D antibody improves	SEMA4D antibody + DC-1 improves		1×104			1×105
	4×103			3×104
DC trafficking in untreated tumor	CD4+ T cell infiltration in tumors		2×103			2×104
			1×104
			0			0

Key Exclusion Criteria

• Patients with uncontrolled brain metastases or

leptomeningeal disease

1	3-6	0.05	- 0.25 x 109	0.05	- 0.25 x 109
2	3-6	0.25 - 1.20 x 109	0.25 - 1.20 x 109
3	3-6	0.50 - 2.50 x 109	0.50 - 2.50 x 109
-1	NA	0.005	- 0.025 x 109	0.005	- 0.025 x 109

survival.

• HER2-specific T cell immune response

• IFN gamma ELISPOT

• Persistence of T cell immunity up to 1 year

following the last infusion

• Biomarker analysis

consist of 3-6 patients each with increasing amounts of transferred CD4+ T cells, followed by dose expansion of 10 patients at the MTD. The primary objective is safety and tolerability; secondary objectives will include evaluation of T cell immunity and immune subsets, efficacy, PK/PD/ADA of pepinemab, and biomarker assessments.

REFERENCES

1. Lowenfeld L, Mick R, Datta J, Xu S, Fitzpatrick E, Fisher CS,Fox KR, DeMichele A, Zhang PJ, Weinstein SP, Roses RE, Czerniecki BJ.

Dendritic Cell Vaccination Enhances Immune Responses and Induces Regression of HER2pos DCIS Independent of Route: Results of

Randomized Selection DesignTrial. Clin Cancer Res. 2017 Jun 15;23(12):2961-2971.

CD11c+		DC trafficking- 24h
10		✱✱
II+	8					✱✱
Class
	✱✱✱
6
violet	4					✱
trace	2
% Cell	0
Control	-DC1		Control	-DC1
		HER2 -Sema4D	HER2 -Sema4D
	-DC1+Anti		-DC1+Anti
HER2			HER2

	CD4
Treated Tumor	Untreated Tumor

SEMA4D antibody + DC-1 + CD4+ T cell adoptive therapy

improves tumor regression

			Control						Adoptive T cell					Adoptive T cell
										+ DC-1					+ DC-1 + SEMA4D MAb
400								400									400
300							2	300								2	300
						Area mm								Area mm
200							200								200
100							Tumor	100								Tumor	100
0								0									0
0	10	20	30	40	50	60	70	0	10	20	30	40	50	60	70		0	10	20	30	40	50	60	70
											Days								Days

•	Female patients who are pregnant or nursing
•	are not eligible
Second invasive malignancy requiring active
	treatment

• Blood collection and IV transfer for each, anti-HER2 CD4 Th1 cells expanded with either IL-15 or IL-7, will occur 1 week apart
  • Treatment with cyclophosphamide (300mg/m2) administered 1 day prior to first expanded CD4+T cells

• The first 2 patients in each dose escalation cohort will be enrolled with staggering interval of 14 days.

A total of 10 patients will be enrolled into the dose expansion cohort and will be treated with CD4+ T cells at MTD. MTD will be defined as the highest dose tolerated leading to dose-limitingtoxicities (DLTs) in <2 of 6 patients.

• Characterize immune cell composition,

including MDSC, Th2 and Treg.

2.	Patnaik A, Weiss GJ, Leonard JE, Rasco DW, Sachdev JC, Fisher TL, Winter LA, Reilly C, Parker RB, Mutz D, Blaydorn L , Tolcher AW,
	Zauderer M, Ramanathan RK. Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-
	Human Study of Patients with Advanced Solid Tumors. Clin Cancer Res. 2016 Feb15;22(4):827-36.
3.	Clavijo PE et al. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and
	Function. Cancer Immunol Res. 2019 (2):282-291.
4.	Evans EE, et al. Antibody Blockade of SEMA4D Promotes Immune Infiltration into Tumor and Enhances Response to Other
	Immunomodulatory Therapies. Cancer Immunol Res. 2015 (6):689-701.
5.	Shafique MR, Fisher TL, Evans EE, Leonard JE, Pastore DRE,Mallow CL, Smith E, Mishra V, Schröder A, Chin KM, Beck JT, Baumgart MA,
	Govindan R, Gabrail NY, Spira AI, Seetharamu N,Lou Y, Mansfield AS, Sanborn RE, Goldman JW, Zauderer M. A Phase Ib/II Study of
	Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res. 2021Jul 1;27(13):3630-3640.

Preclinical spontaneous tumor model in NeuT transgenic mice

Status:

ENROLLING NOW

This study was approved by Advarra; approval number IRB#00000971	Sponsor: H. Lee Moffitt Cancer Center and Research Institute
NCT05378464	Collaborator: Vaccinex Inc.

FORWARD LOOKING STATEMENTS: To the extent that statements contained in this information as presented are not descriptions of historical facts regarding Vaccinex, Inc. ("Vaccinex," "we," "us," or "our"), they are forward-looking statements reflecting management's current beliefs and expectations. Such statements include, but are not limited to, statements about our plans, expectations and objectives with respect to preclinical research and clinical trials, and other statements identified by words such as "may," "will," "expect," "anticipate," "estimate," "intend," "potential," "advance," and similar expressions or their negatives (as well as other words and expressions referencing future events, conditions, or circumstances). Forward-looking statements involve substantial risks and uncertainties that could cause our research and pre-clinical development programs, clinical development programs, future results, performance, or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, uncertainties inherent in the execution, cost and completion of preclinical and clinical trials, uncertainties related to regulatory approval, risks related to our dependence on our lead product candidate pepinemab (VX15/2503), and other matters that could affect our development plans or the commercial potential of our product candidates. Except as required by law, we assume no obligation to update these forward-looking statements. For a further discussion of these and other factors that could cause future results to differ materially from any forward-looking statement, see the section titled "Risk Factors" in our periodic reports filed with the Securities and Exchange Commission ("SEC") and the other risks and uncertainties described in our Form 10-K dated March 13, 2019 and subsequent filings with the SEC.

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