Vaccinex : ASCO Conference Presentation

Correlative and spatial biomarker analysis of a phase 1/2b study to evaluate

PEPINEMAB IN COMBINATION WITH PEMBROLIZUMAB for first-linetreatment of patients

with recurrent or metastatic head and neck cancer

#2603

Elizabeth E. Evans1, Terrence L. Fisher1, Crystal Mallow1, Amber Foster1, John E. Leonard1, Marya F. Chaney2, Tarek Mekhail3, Nagashree Seetharamu4, Conor Steuer5, Nabil F. Saba5, Douglas Adkins6, J. Thaddeus Beck7, Alain Algazi8, Barbara Burtness9, Megan Baumgart10, Steven Hager11, Christopher Chay12, Alexander Spira13, Ellen Giampoli 10, and Maurice Zauderer1

1Vaccinex, Inc., Rochester, NY; 2Merck & Co, Inc., Rahway, NJ; 3Advent Health Cancer Institute, Orlando, FL; Zuckerberg Cancer Center, 4Northwell Health, New Hyde Park, NY; 5Emory University ,Atlanta, GA; Emory University Winship Cancer Institute, Atlanta, GA; 6Washington University School of Medicine, St. Louis, MO; 7Highlands Oncology Group, Springdale, AR; 8University of California, San Francisco, San Francisco, CA; 9Yale University School of Medicine and Yale Cancer Center, New Haven, CT; 10University of Rochester, Rochester, NY; 11California Cancer Associates for Research and Excellence, San Diego, CA; 12Cancer Care of Western North Carolina, Asheville, NC; Virginia Cancer Specialists, Fairfax, VA

Pepinemab in combination with Pembrolizumab

KEYNOTE-B84

• Single-arm,open label, phase 1b/2 study
• Analysis stratified by PD-L1 status
• 18 medical centers in USA

Inclusion: pathologically confirmed R/M SCC; ECOG ≤ 1, immunotherapy naive

Exclusion: progressive disease within 6 months of curatively intended systemic treatment given for locoregionally advanced disease, symptomatic CNS metastases, active autoimmune disease.

Study design mimics KEYNOTE-048.

Treatment	Phase 1b Safety	Phase 2 Efficacy	Outcome Measures
20mg/kg pepinemab		Pre-specified Interim Analysis	Safety
+ 200mg pembrolizumab, Q3W		(36 patients)	Objective Response
		Current Enrollment 49 patients	Biomarker Outcomes

KEYNOTE-B84(NCT04815720) is an ongoing single-armopen-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of recurrent or metastatic HNSCC. Exploratory biomarker analyses were performed to evaluate spatial interactions of tumoral immune cells. Pre- and on-treatment tumor biopsies were collected and assessed by multiplex immunohistochemistry for up to

36 biomarkers/biopsy. Unbiased algorithms identified co- localization of markers for advanced cell phenotyping, density, spatial and proximity analysis. Biomarker results were then stratified by demographic and clinical outcome measures.

Background

Safety

Biologic Activity

Efficacy

Clinical Benefit in

Increased ORR and DCR in

Altering the balance of suppressive myeloid

Treatment Induced

Presence of Mature TLS Correlates

Hard-to-treat Populations

Hard-to-treatPD-L1 low

KN-B84

KN-048

to Antigen Presenting Cells

Mature Immune Aggregates

with Disease Control

56% of HPV negative

Disease Control Progressive Disease

✱✱✱✱

"cold tumors" showed

Pepi+Pembro

Pembro

100

Progression-free survival

~2x

Activated APC

cells/AggregateB (mean+SEM)

✱✱✱✱

100

induction of TLS after

identified. Pepinemab

80

0

treatment

DCR

21%

11%

CD68)

ORR

HLA-DR+ (CD11c and

Tumor

60

50

TLS

Progression-Free Survival

Pan-Cytokeratin+

No concerning or

MDSC

40

ns

**

Increased in PD-L1 low CPS 1-19

~2x

Arg1+ CD14 and CD15

No TLS

unexpected safety signals

20

74%

37%

does not add toxicity to

0

0

5

10

PreTx OnTx

PreTx OnTx

pembrolizumab

Disease Control

Disease Progression

Time(months)

						Patients who experience clinical benefit (Disease Control) during	B cell aggregates correlate with PFS. On-treatment	PFS
AEs appear to be either disease-	Treatment appears to reverse the immunosuppressive tumor	8.2mo	2.2mo
treatment with pepinemab and pembrolizumab have a higher	biopsies with one or more B cell aggregates positively
related or prior medical history	microenvironment in patients who experienced clinical
benefit, compared to those with progressive disease.	frequency of mature immune aggregates with a high density of B	correlates with longer progression-free survival. N=12 on-
related and are low grade						cells in their on-treatment biopsy (n=7) compared to their pre-	treatment biopsies at interim analysis. Log Rank survival
(Grade 1-2)						treatment biopsies (n=16), p<0.0001. One-way ANOVA, ****	statistical analysis resulted in a ** p value of 0.0056.
						p<0.0001; ns = not significant, p≥0.05.

Myeloid cells contribute to suppression of adaptive immunity within the TME and limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Semaphorin 4D (SEMA4D) signaling through its receptors (PlexinB1/B2,CD72) promotes recruitment and suppressive function of myeloid suppressor cells (MDSC).1 Blocking antibody to SEMA4D attenuated MDSC and increased penetration and organization of dendritic cells (DC) and T cells into tertiary lymphoid structures that enhanced activity of ICI in preclinical and clinical studies.1,2 Pepinemab, in combination with anti-PD-L1 was well tolerated and provided clinical benefit in patients with ICI-resistant,PD-L1-low NSCLC3. We hypothesize that SEMA4D blocking antibody pepinemab may regulate infiltration and crosstalk of immune cells in

Results

• An increase in the balance of activated APC (HLA-DR+CD11c+ and HLA-DR+CD68+) to suppressive MDSC (Arg1+CD14+ and ARG1+CD15+) was observed in patients with durable disease control.
• Combination therapy induced the formation of highly organized immune aggregates, including a high density of activated B cells, DC's, CD4+ and CD8+ T cells, including stem-like CD8+TCF1+PD1+ T cells.
• Presence of immune aggregates increased in on-treatment compared to pre-treatment biopsies, even in HPV-negative and PD-L1 low tumors.
• Favorable spatial interactions between DC-1, CD8, CD4, and B cells was associated with PFS and disease control.

Combination therapy induced formation of highly organized	Combination Therapy Reprograms
immune aggregates with Key Immune Cells for Antigen Presentation	Cold Tumors to Hot Tumors,
and Expansion of T cells	Induces TLS and
TLS in Matched Biopsy Pairs	Immune Aggregate Organization	Correlates with Disease Control

	2.5	P = 0.0858	Disease Control (CPS <20)	Progressive Disease (CPS ≥20)	Disease Control
				CPS lo	CPS hi
	2.0
TME							Avg
				Screen	OnTx	Screen	Density (mm^2 TME)

TME as a novel and complementary mechanism of immune enhancement when combined with immune checkpoint therapy.

	SEMA4D		Anti-SEMA4D
	Immune Suppression	Immune Enhancement
		1
			4
	2		3
			Created with BioRender.com
		TLS	Immune Attack/
		Tumor Death
• Ligand SEMA4D expressed on
Pepinemab in combination with pembrolizumab
	Tumor and/or Lymphocytes
•
Receptor Plexin B1/B2 (PLXN)	1) Activates Dendritic Cells
•	expressed on Myeloid cells	2) Induces Tertiary Lymphoid Structures
Ligand:Receptor engagement
(TLS)
	induces recruitment /
	3) Expands T cells in Tumor
•	suppressive Myeloid function
Inhibit T cell function	4) Reverses Myeloid Immunosuppression

Treatment Induced Dendritic cells, B cells and T cells within the TME in Disease Control Patients

CD11c+CD68+Density/mm^2 TME		MacDC			CD11c+ DC	(DCR)(PD) High
500	✱	CD11c+Density/mm^2 TME	1000	P = 0.0640
		TLS Density
400		800
		B cell
300	Screen OnTx Screen OnTx	600	Screen OnTx Screen OnTx	CD8			AvgDensity
	200			400		CD8CD69
	100			200		CD4(FP3-)
				CD68
				0
	0				CD68HLADR
		B cells			CD8+ T cells	CD11cCD68			(mm^2TME)
TME/mm^2	300	TME/mm^2	1500	CD11cCD141
	✱
	500			2500	CD11cCD68HLADR
					CD11c
	400
			2000		CD11cHLADR
CD20	200		CD8+	1000		CD11cCD141HLADR			Low
Density	100		Density	500		Total APC HLADR+
				Screen		Screen
	0	Screen OnTx Screen OnTx	0	Screen OnTx Screen OnTx	OnTx	OnTx

OnTx Biopsies show

higher Stem-Like CD8 in

Disease Control

TME	5		✱✱✱
TCF1+PD1+CD8+cells/mm^2	0
	4
	3
	2
	1
		DCR	PD

Stem-like CD8 are associated with improved response to immunotherapy and share features with TFH cells found within immune aggregates. Patients with disease control had a higher density of stem-likeCD8 T cells after treatment within the TME. Statistical analysis: Two tailed unpaired t test, P<0.05

/ mm^2	1.5									TLS Density	High
1.0									B cell
TLS
									CD8
#	0.5
								CD8CD69
								T cells	Low
	0.0								CD4(FP3-)
								CD4(FP3-)CD69
	PreTx OnTx	PreTx	OnTx
	DCR	PD	DC	T cell	Stem-Like T cells	CD4 T helper cell	Treg	B cells	CD4FP3
	n=7	n=5
		All CD11c+	CD8+	CD8+ TCF1+	CD4+FoxP3-	CD4+FoxP3+	CD20+

		Stem-like CD8	Disease Control	Progressive Disease		CD68
			CD68HLADR
	within Immune Aggregates	TLS Density /mm^2 Colors indicate % cell makeup		APCs	CD11cCD68
			Progressive		CD11cCD68HLADR
CD8+TCF1+PD1+ cells / B cell aggregate	20	Disease Control	● CPS	CD11c
		Disease	<20	CD11cHLADR
15			○ CPS	CD11cCD141
		≥20
			CD11cCD141HLADR
10
			n=10	n=7	n=7
5
0
	CR03PR02SD03SD04SD06SD09SD11PD02PD04PD05PD06PD09	Patients experiencing disease control following treatment with pepinemab plus pembrolizumab showed an		Patients with PD-L1 low (CPS < 20) tumors have lower TLS, B cells, T
	increase in the number of B cell aggregates (above). These aggregates exhibit spatial organization that is
	characteristic of functional immune response, similar	to mature TLS. Highly organized immune		cells and APCs than PD-L1	high	(CPS ≥ 20) disease before

Tumor Response

~ 2x increase in ORR, DCR, and PFS in

CPS <20 with pepi+pembro combination treatment, compared to historical control7

Disease control patients (DCR include: CR, PR, SD) show an increase in important	Disease Control (DCR)
inflammatory immune cell subsets when treated with pepinemab plus pembrolizumab.	Screen n=17, OnTx n=8
MacDc and CD8 T cells had the most significant increase with treatment. Statistical	Disease Progression (PD)
analysis: Two tailed unpaired t test, P<0.05	Screen n=11, OnTx n=6

	aggregates contain zones of high-density APCs (activated DC, B cells) and a T cell zone with CD8, CD4 T	treatment. After combination treatment, PD-L1 low patients
TCF1+PD1+CD8+ Stem-like progenitor cells	helper cells and stem-like CD8's. In contrast, patients with progressive disease and untreated patient tumors	demonstrate increased density of immune cells needed to mount a
appear to be associated with Disease	predominantly contain no or few immune aggregates with spatial interactions that favor immune	robust immune response, including B cells, T cells and APCs, along
Control and located within B cell aggregates	suppression, including abundance of Treg. Remarkably, TLS were induced in HPV-negative HNSCC, which	with an induction of TLS that correlate with durable disease control.
	typically have low TLS and lower disease control rates.

		CPS <1				CPS 1-19			CPS <20		CPS ≥20
	KN-B84		KN-048		KN-B84	KN-048		KN-B84	KN-048	KN-B84	KN-048
	Pepi + Pembro	Pembro	Pepi + Pembro Pembro	Pepi + Pembro Pembro	Pepi + Pembro Pembro
Total		(6)		44		(13)	(124)		(19)	(168)		(17)	(133)
CR	1	16.7%		0.0%	1		7.6%	3.2%	2	10.5%	2.4%	1		5.9%	7.5%
PR	0	0%		4.5%	2		15.4%	11.3%	2	10.5%	9.5%	2		11.8%	15.8%
SD	2	33.3%		22.7%	8		61.5%	25.8%	10		52.6%	25.0%	5		29.4%	30.1%
ORR	1	16.7%		4.5%	3		23.1%	14.5%	4		21.1 %	11.9%	3		17.6%	23.3%
DCR	3	50.0%		27.3%	11		84.6%	40.3%	14		73.7%	36.9%	8	47.1%	53.4%

Novel and Independent Mechanism of Pepinemab

Results suggest that combination therapy	Similar observations in separate trial for patients with	Evidence of treatment-induced biologic activity
induced formation of highly organized lymphoid	metastatic melanoma, supporting that combination	corresponding with disease control and suggests a novel
aggregates in HNSCC tumors, with a high	immunotherapy with pepinemab induces mature	and independent mechanism of pepinemab to enhance
density of activated B cells, DC and T cells.	lymphoid structures within the TME2.	immune interactions and ICI activity.

To the extent that statements contained in this presentation 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 the Company's plans, expectations and objectives with respect to the results and timing of clinical trials of pepinemab in various indications, the use and potential benefits of pepinemab in cancer, Huntington's and Alzheimer's disease and other indications, and other statements identified by words such as "may," "will," "appears," "expect," "planned," "anticipate," "estimate," "intend," "hypothesis," "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 the outcome of the Company's 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, the risks related to the Company's dependence on its lead product candidate pepinemab, the ability to leverage its ActivMAb® platform, the impact of the COVID-19 pandemic, and other matters that could affect the Company's development plans or the commercial potential of its product candidates. Except as required by law, the Company assumes no obligation to update these forward-looking statements. For a further discussion of these and other factors could cause future results to differ materially from any forward-looking statement, see the section titled "Risk Factors" in the Company's periodic reports filed with the Securities and Exchange Commission ("SEC") and the other risks and uncertainties described in the Company's most recent year end Annual Report on Form 10-K and subsequent filings with the SEC.

REFERENCES

1. Clavijo PE et al. Cancer Immunol Res. 2019 (2):282-291.
2. Olson B et al. Journal for ImmunoTherapy of Cancer 2022;10.
3. Shafique MR et al. Clin Cancer Res. 2021 Jul 1;27(13):3630-3640.
4. Rossi AJ et al. Ann Surg Oncol 28, 4098-4099 (2021)
5. Ruffin AT et al. NATURE COMMUNICATIONS (2021) 12:3349.

1. Labroots webinar: Tertiary lymphoid structures to the forefront of
   immunotherapy: what are they good for? Tullia C. Bruno, PhD Assistant Professor, University of Pittsburgh, Hillman Cancer Center
2. NCT02358031. Burtness et al. 2022 Clinical Oncology 40 (21): 2321-
   2332. NOTE: CPS <20 was calculated post-hoc from analysis of CPS<1 and 1-19 assessments; these do not represent alpha controlled

analyses

1. Fisher et al, Cytometry Part B, 2016; 90B, 199-208
2. Harmonize inclusion / exclusion criteria of KEYNOTE-048 Phase 3 study, reference for historical comparison of single agent KEYTRUDA

Contact: [e-mail]