ANGN BIOM : ELI-002 Immunotherapy Induces Broad Polyfunctional T cell Responses in Subjects with High Relapse Risk KRAS Mutated Pancreatic Ductal Adenocarcinoma and Colorectal Cancer (SITC – Scientific Poster)

November 02, 2023

Presented at the SITC 38th Annual Meeting, 3-5 November 2023, San Diego, CA, USA, and online	Abstract 656

ELI-002 Immunotherapy Induces Broad Polyfunctional T cell Responses in Subjects with High

Relapse Risk KRAS Mutated Pancreatic Ductal Adenocarcinoma and Colorectal Cancer

James R. Perry1, Lochana M. Seenappa1, Haley VanWyk1, Amy M. Tavares1, Thian Kheoh1, Esther Welkowsky1, Christopher M. Haqq1, Peter C. DeMuth1,

and Lisa K. McNeil1

1 Elicio Therapeutics, Inc. 451 D St., Ste 501, Boston, MA 02210

Why Target mutated KRAS with Therapeutic Vaccination?

mKRAS T Cell Responses Correlate with Reduction in Risk of Relapse or Death13

Expansion of mKRAS-specific T cells by ELI-002 2P Immunization

1 Mutant KRAS Drives 25% of Solid Human Cancers

Prevalent among numerous tumor types1-2

Overall poor clinical prognosis3

Limited therapeutic options

2 Mutant KRAS is a Promising Tumor Antigen

Truncal: mutations occur early, expressed uniformly in all tumor cells

Driver: mKRAS signaling is required for tumor growth and survival

Highly prevalent: involved in ~25% of solid tumors1-2

Public neoantigen: not centrally tolerized, cognate TCRs present in naïve repertoire4-5

Promiscuous HLA presentation: potential off-the-shelf use in diverse patient population6-8

Proven Clinical MOA: mKRAS-specific T cells known to mediate anti- tumor efficacy4-5

Multi-targetingpotential: recognition of clonal and subclonal mKRAS variants to prevent escape9

KRAS mutant

NRAS mutant

52%	93%

Colorectal Cancer (CRC)	Pancreatic Ductal
US Incidence: 151k	Adenocarcinoma
	(PDAC)
	US Incidence: ~56k

Strength of T Cell Response	86% Reduced Risk of Relapse or Death		Tumor Biomarker Response
(%)Survivalfree-Relapse								ResponseBiomarkerOverall	Baseline)of(%	300

100				Median RFS: not reached					P = 0.0017
							200
75										✱✱

50										100

25				Median RFS: 3.91 months		Best		0

									-100
Months 0
0	3	6	9	12	15	18			≥ Median	< Median
										T Cell Response
≥ Median T Cell Response (n = 12)	P = 0.0134			Best Overall Tumor	Clearance
< Median T Cell Response (n = 10)	HR: 0.138 (0.031 - 0.610)		Biomarker Response	Reduction
	Non-Responder

	450	Fold-change		Ex Vivo Fluorospot		Ex Vivo ICS
		and/orγIFN GrB SFC		1300	among	T cells	4	0.1 mg
	50			200
Foldchange frombaseline		PBMC	2	0.5 mg
			1.0
30		150	+		2.5 mg
Median:	1x10/		Cytokine%	CD8
	10	13x		6	100	+	CD4or	0.5	5.0 mg
						+
	5				50				10.0 mg
	0		Max		0	Max		0.0	Max
		Baseline		Baseline		Baseline
		Response		Response		Response

87% of Patients generated direct ex vivo detectable mKRAS-specific T cell responses following ELI-0022P Immunization, with 100% Responders at the highest dose levels (5.0 and 10.0 mg)

Ex Vivo Responders	CD4 / CD8 Response	Specificity	Specificity
13	13		10	10	20
		35
	50	25		5


87	38		30	65

Responders	CD4 + CD8 T cells	7 antigens	G12R Responses
Non-responders	CD8 T cells	5-6 antigens	G12D Responses

ELI-002 2P: Advancing Innovation for mKRAS Cancer Vaccines

1 Technological Innovation: Amphiphile Lymph Node Targeting Platform10-11		2 Clinical Innovation: Treatment in High Relapse-Risk Adjuvant Setting

Smart trafficking to the lymph nodes after subcutaneous dosing generates		Targeting surgically debulked tumors enables T cells to address minimal residual
immune responses with increased magnitude, function, and durability.		disease to potentially eliminate remaining tumor cells and protect against
Takes advantage of potent lymph node immune mechanisms, including activation		recurrence.
	Activating the immune system before loss of HLA expression in the tumor
of innate and adaptive cells, antigen-spreading, and improved tumor T cell
trafficking / infiltration.		microenvironment in a chemotherapy-free window of opportunity.
Mutant KRAS peptides provide a validated antigen for application of the		Other oncology vaccines have typically been used in later lines of therapy for
Amphiphile platform.		advanced disease, after onset of tumor immune resistance.
Lymph node delivery of potent adjuvants minimizes systemic exposure to		In the adjuvant setting, tumor biomarkers (ctDNA, serum tumor antigen) are
improve safety.		early predictors of disease control or recurrence.

Amphiphile mKRAS Long			12
ELI-002 2P	Peptide Antigens	O

1	Amph-mKRAS G12D		O

2	Amph-mKRAS G12R	Albumin Binding Lipid	PEG Linker	G12D or G12R Peptide
Amphiphile TLR-9 Agonistic	O
	NH
	DNA Adjuvant		O
			NH
	Amph-CpG-7909	Albumin Binding Lipid	CpG-7909 DNA

Inclusion of 18-mer G12D and G12R mKRAS peptides allows for delivery of diverse HLA I and II - restricted epitopes for presentation on varied patient HLA molecules.

Amphiphile (Amph)-modificationof peptides promotes binding to endogenous albumin at the injection site to promote collection in lymphatic vessels for lymph node delivery, and prevents peptide uptake into local capillaries avoiding delivery to irrelevant or tolerogenic sites.

Amph-CpG-7909provides potent immune activation via TLR-9 stimulation of lymph node-resident professional antigen presenting dendritic and other key immune cells.

Tissue Injection Site	Lymph Node
Amphiphiles	Endogenous Albumin	Albumin-bound Amphiphiles



	Albumin-bound Amphiphiles			Antigen Presenting Cell	T Cell
1 Subcutaneous	2	Albumin	3	Lymph node	4	Delivery to
injection		binding		targeting		immune cells

Conventional vaccine components (e.g. peptide antigens and molecular adjuvants) are rapidly absorbed into blood capillaries after administration leading to poor delivery to lymph nodes where protective immune responses are orchestrated.

Amph-modification promotes albumin binding to reprogram vaccines for enhanced lymph node delivery resulting in coordinated transport of antigen and adjuvant to immune cells. Improved uptake by Antigen Presenting Cells results in enhanced antigen-presentation and co-stimulation to cognate T cells.

Restricted delivery to lymph nodes minimizes systemic exposure to avoid toxic effects of potent adjuvants.

Patient #23: mKRAS-specific T cell Profile - Ex Vivo Fluorospot

	250	G12R		1000	G12V		1000	WT KRAS
and/orIFNγ GrB SFC 1x10/		1x10/		and/orIFNγ GrB SFC	1x10/
200	and/orIFNγ GrB SFC	800		800
PBMC	150		PBMC	600	G12A	PBMC	600
6			6		G12S	6
	100			400		400
			G13D
	50			200		200

	0			0			0

Week	B	9	Week	B	9	Week	B	9

Week 9		Week 9
	IFNγ+		IFNγ+	• Elevated T cell responses to G12R

			and G12D by Week 9 after prime
	GrB+		GrB+		immunization series

99	IFNγ+ GrB+	99	IFNγ+ GrB+	• No responses were observed to

		99			the WT antigen

Patient #23: mKRAS-specific T cell Profile - Ex Vivo ICS Assay

		8	G12R	CD8 T Cells: Week 9			G12R-Specific CD8: Week 9
	cells
+	6	G12D		IFNγ+		mKRAS-specific, Cytokine+
Cytokine%	T	2		10				48
amongCD8		2+			12		12
	+
		4		42	TNFα+	24		24		16
				41
				7	3+
		0
							Naïve			Effector Memory
Week	B	9

								Central Memory		TEMRA
		3	G12R	CD4 T Cells: Week 9			G12R-Specific CD4: Week 9
+	Tcells
	G12D		IFNγ+		mKRAS-specific, Cytokine+
Cytokine%	CD4among	2		38	2+			28	52	31
	+			15	IL2+			20		4 14
				44	α	+
		1			TNF	51

		0		3	3+

Week	B	9

Patient #23 mKRAS-specific Memory T cell Profile - IVS

CD4 T cells

2-4 antigens

G12R + G12D Responses

Responders

1 antigen

Neither

(n = 20)

(n = 3)

G12R

Amph-

ex vivo T cell

Average

CpG Dose

response

fold-

Number of mKRAS

antigens/patient

G12D

Level

(n, %)

change

G12V

0.1 mg

2/3 (67%)

G12C

0.5 mg

5/6 (83%)

G12A

2.5 mg

4/5 (80%)

113

G12S

5.0 mg

5/5 (100%)

G13D

10.0 mg

4/4 (100%)

No Response

Total

20/23 (87%)

Cohort 1 1 2 2 2 2 2 3 3 3 3 4 4 4 4 4 5 5 5 5 1 2 3

CD4 and CD8 T cell responses were observed, with 50% generating mixed CD4 + CD8 responses
mKRAS-specific T cells were polyfunctional (IFNγ, TNFα, IL-2), specific to both immunizing and non-immunizing mKRAS antigens

Increased mKRAS-specific Memory T cells Assessed by IVS

baselinefromchangeFold	100	Fold-change		IVS Fluorospot	cellsT	40	IVS ICS
			4500			0.1 mg
150		SFCαTNFand/orγIFN	1x10/	Cytokine%	CD8among	60
	50			PBMC	500	+	+	20	0.5 mg
	20			400	8		2.5 mg
			6	CD4 or
	25							10
	15				300		+	6	5.0 mg
	10				200			4	10.0 mg
	5				100			2

	0		Max		0	Max		0	Max
		Baseline		Baseline			Baseline
		Response		Response			Response

100% of patients induce mKRAS-specific memory T cell responses after in vitro stimulation

Increased Polyfunctionality of mKRAS-specific T cells after ELI-002 2P Immunization

•	Patient #23	T Cell Activation: Week 9	Cytolysis: Week 9	Proliferation: Week 9

Polyfunctional T cell Profile:
Increased activation,

cytolysis, and

CD8

0.71

CD4

7.81

CD4

5.02

proliferation after

vaccination

CD137

GrB

Ki67

ELI-002 2P Immunization Elicits Durable mKRAS-specific Immune Responses

2000

Patient 16

• ELI-002 2P vaccination generates long-lasting mKRAS-

AMPLIFY 201: Trial Design12

Prior Therapy	Screening Period	Amph-Peptides 2P 1.4 mg + 0.1, 0.5, 2.5, 5 or 10 mg Amph-CpG-7909
Locoregional	mKRAS+	Prime	No Dosing	Booster	Follow-up
G12R+ or G12D+
Therapy:	Immunization	Period	Immunization		Period

Surgery	NED
+	Imaging Negative	Week S/B 0 1 2 3 4 5	6 7 8 9 17	20 21 22 23 24	25	105
Neoadjuvant /	MRD+
Dose
Adjuvant
ctDNA+ or	ctDNA
Chemotherapy
	serum biomarker+	Serum biomarkers

PBMC


Patients	Baseline Characteristics: 20 Pancreatic (PDAC), 5 Colorectal (CRC) were evaluated for safety as of data cutoff: April 25, 2023

Safety	Safety:	No TEAEs ≥ Grade 3, no Dose Limiting Toxicities, no Cytokine Release Syndrome observed across all dose levels;
	44% had Grade 1-2 TEAEs: e.g. injection site reaction, fatigue, headache, nausea12

AMPLIFY 201: Immunogenicity Methods

• Immunogenicity of ELI-0022P was assessed using longitudinally collected peripheral blood from 23 evaluable patients to assess specificity, polyfunctionality,

antigen breadth, and phenotype of mKRAS-specific T cells.

		2500
SFC	PBMC	2000
TNFα
1500
	6
IFNγand/or / 1x10	1000
500
			0
	Week	B	9
			4
	+	cells	3
	% Cytokine	T
	+
	among CD8	2
	1
			0
	Week	B	9

G12R G12D

% Cytokine Secretion in	SFC		1000						WT KRAS


Fluorospot: Week 9	PBMC	800


			IFNγ+	TNFα	600



			6
27	27		IFNγ+ TNFα+	and/orIFNγ	1x10/

46			200
			TNFα+			400

						0







					Week		B	9

		15		G12R
	cells
+			G12D	• After IVS stimulation, greatly

Cytokine%	CD4among	10			increased T cell responses to G12R
	T				and G12D at Week 9 post prime
	+
					immunization series
		5			• No responses were detected for the

					WT antigen
		0
Week	B	9

SFC		1500					Patient 18	specific T cell responses
PBMC	1000

				Patient 20
600					• 100% (4/4) of evaluable patients maintain elevated T

GrB	6
and/or	1x10	450					Patient 11	cell responses above baseline post-boost immunization

300
IFNγ	/						• An increased post-boost T cell response was observed
150
							in 75% (3/4) of evaluable patients compared to pre-
		0	5	10	15	20	25	boost T cell levels
		0
				Weeks post-vaccination

	T Cell Response	 86% Reduced Risk of Relapse or Death
MESSAGES	MOA Correlated to:	 Tumor Biomarker Response
Lymph node-targeted Therapeutic mKRAS-specific Cancer Vaccine ELI-002 2P:
 Direct ex vivo mKRAS-specific T cell responses observed in 87% of patients
and IVS responses were observed in 100% of patients
HOME	 50% of patients generated both CD4 and CD8 T cell responses
 T cells exhibited robust functional quality: activation, cytokine production,

• PBMCs from each patient were individually stimulated with overlapping peptides for each of the seven mKRAS antigens (G12R, G12D, G12V, G12C, G12A,

G12S and G13D) and the WT antigen, for evaluation of mKRAS-specific T cell responses using both direct ex vivo and in vitro stimulated assays.

• T cell responses and polyfunctionality were determined by a direct ex vivo IFNγ/Granzyme B (GrB) Fluorospot and a 10-dayin vitro stimulated (IVS)

IFNγ/TNFα Fluorospot assay, where a positive immune response was defined as >2-fold over baseline and at least 50 SFC per million PBMCs.

• Polyfunctionality and phenotype of patient T cells were further characterized using an ex vivo and IVS intracellular cytokine staining (ICS) assay, where

responder populations were defined as >2-fold over baseline and a frequency of at least 0.1% Cytokine+. The ICS assay included markers for CD3, CD4, CD8,

Memory (CCR7, CD45RA, CD45RO), cytokines (IFNγ, TNFα, IL2), cytolysis (GrB, Perforin, CD107a), activation markers (CD69, CD137, CD154), and proliferation

(Ki67).

References

1.	Bianken A, et al. Nature. 2012; 491(7424): 399-405	5.	Tran E, et al. NEJM. 2016; 375(23): 2255-2262	9.	Awad MM, et al. Cancer Cell. 2022; 40(9): 1010-
2.	Prior IA, et al. Cancer Research. 2012; 72(10):	6.	Bear AS, et al. Nat. Commun. 2021; 12(1): s41467-		1026
	2457-2467		021-24562-2	10.	Liu H, et al. Nature. 2014; 507: 519-522
3.	Siegel RL, et al. Cancer J. Clin. 2021; 71(1): 7-33	7.	Carbone DP, et al. J Clin Oncol. 2005; 23(22): 5099-	11.	Moynihan KD, et al. Nature Medicine. 2016;
4.	Leidner R, et al. NEJM. 2022; 386(22): 2112-2119		5107		22(12): 1402-1410
		8.	Palmer CD, et al. Br. J. Cancer 2020; 122(7): 971-977	12.	O'Reilly EM, et al. J Clin Oncol. 2023; 41(16): 2528

				13.	Wainberg Z, et al. 2023 AACR Special Pancreatic.

Acknowledgements			2023

• We are grateful to the patients who participated in the study, their families, and the investigators and staff at the participating institutions.

	cytolytic capacity, proliferation, memory phenotype
	100% (4/4) of patients evaluable for durability maintained elevated T cell
TAKE	responses above baseline

 Phase 1, randomized Phase 2 Study of ELI-002 7P (NCT05726864) in PDAC patients: targeting G12D, R, V, C, A, S, G13D

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Elicio Therapeutics Inc. published this content on 03 November 2023 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 10 November 2023 14:37:53 UTC.

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