NEON. Directing the Immune System THERAPEUTICS. January Neon Therapeutics

Transcription

1 NEON THERAPEUTICS Directing the Immune System January

2 Forward-Looking Statements and Intellectual Property Forward-Looking Statements This presentation may contain forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our clinical results and other future conditions. All statements other than statements of historical facts contained in this presentation, including statements regarding our future financial or business performance, conditions, plans, prospects, trends or strategies and other financial and business matters; our current and prospective product candidates, current and planned clinical trials and preclinical activities, research and development costs, current and prospective collaborations; the estimated size of the market for our product candidates, the timing and success of our development and commercialization of our anticipated product candidates; and the availability of alternative therapies for our target market. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Intellectual Property Neon Therapeutics, Inc. is the owner of the NEON THERAPEUTICS, RECON, and NEO-STIM trademarks, as well as certain other trademarks, including design versions or some of all of these trademarks. The symbols and are not used in connection with the presentation of these trademarks in this presentation and their absence does not indicate a lack of trademark rights. Certain other trademarks used in this presentation are the property of third-party trademark owners and may be presented with or without trademark references. 2

3 Neon Therapeutics OUR MISSION To be a breakthrough oncology company creating neoantigen-based therapeutics to significantly improve patients lives LEADING NEOANTIGEN PLATFORM MULTIPLE THERAPEUTIC MODALITIES PIONEERING CLINICAL DEVELOPMENT WELL CAPITALIZED Leverage our core platform capabilities to rigorously advance the science of neoantigens Explore both vaccine and cell therapy products to maximize reach across a broad spectrum of cancer patients First neoantigen clinical trial in metastatic setting, demonstrating broad immune response in combination with checkpoint inhibitor Cash balance of $122M as of September 30, 2018; funding into Q2:2020, through multiple inflection points 3

4 Neon Founders Pioneered Neoantigen Science OUR FOUNDERS JAMES ALLISON, PHD MD Anderson Cancer Center TON SCHUMACHER, PHD Netherlands Cancer Institute BOB SCHREIBER, PHD Washington University CATHERINE WU, MD Dana-Farber Cancer Institute NIR HACOHEN, PHD Broad Institute GROUNDBREAKING SCIENCE Importance of mutational load in checkpoint inhibition Expansion of neoantigen responses during checkpoint inhibition Effectiveness of neoantigen vaccines in animal models LANDMARK CLINICAL STUDY Ton Schumacher 1 Cathy Wu 2 Ton Schumacher & Marit van Buuren 3 Bob Schreiber & Ton Schumacher 4 1. Rizvi, Science 2015; 2. Van Allen, Science 2015; 3. Van Rooij, JCO 2013; 4. Gubin, Nature 2014 July 2017 ERIC LANDER, PHD Broad Institute ED FRITSCH, PHD Neon; formerly DFCI, Broad 4

5 Experienced Management Team HUGH O DOWD, MBA CEO Novartis RICHARD GAYNOR, MD President R&D Eli Lilly TERESA REGAN VP Human Resources Cubist KELLEDY MANSON VP Product Development Epizyme; Adnexus ROBERT ANG, MD MBA CBO Bavarian Nordic; Cadence JOLIE SIEGEL, JD General Counsel Choate, Hall & Stewart YASIR AL-WAKEEL, BM BCh CFO Merrimack; Credit Suisse 5

6 Neoantigens Represent Ideal Tumor Targets NEOANTIGENS ARE FUNDAMENTAL TO ANTI-TUMOR IMMUNE ACTIVITY (van Rooij et al 2013, Gubin et al 2014, Rizvi et al 2015) BROAD INTIMATELY TUMOR-SPECIFIC CAN BE HIGHLY IMMUNOGENIC APPLICABILITY ACROSS CANCERS Not found on normal tissue Recognized as non-self Ubiquitously found in cancer POTENTIAL DURABLE CLINICAL BENEFIT Multiple targets to avoid escape 6

7 MULTIPLE MODALITIES TO TARGET NEOANTIGENS: Vaccines & T Cells PERSONAL APPROACH NEO-PV-01 NEO-PTC-01 Platform Technologies VACCINES T CELLS NEO-SV-01 + others PRECISION APPROACH TCR-based Therapies 7

8 Progress Across Portfolio NEO-PV-01 Trial NT-001 in Metastatic Disease Direct ex vivo responses in all patients T cells trafficking into tumor Multi-functional T cell phenotypes T cells that recognize and kill tumor Trial NT-002 in 1L NSCLC chemo combo 52-week data in 2H 2019 Trial NT-003 in Melanoma CTLA-4 & CD40L combos PERSONAL APPROACH Platform Technologies NEO-PTC-01 Proof of principle shown at SITC 2018 Multiple CD8+ and CD4+ T cell populations induced in each patient sample Highly functional induced T cells specific for mutant neoantigens In vitro demonstration of tumor cell killing CTA filing in EU expected 1H 2019 VACCINES NEO-SV-01 Highly immunogenic epitopes in ER+ breast subpopulation Proprietary set of peptide immunogens + adjuvant Potential complementarity with CDK4/6 inhibitors and hormonal approaches IND filing 1H 2019 T CELLS TCRs Platform capabilities to: discover & validate epitopes, generate de novo T cell responses and Isolate & characterize TCRs Now characterizing first wave of TCRs Next wave of TCRs can include HLA-B & -C alleles, alongside Class II opportunities Other products in development PRECISION APPROACH 8

9 BROAD APPLICATION OF NEOANTIGEN THERAPIES VACCINES T CELL THERAPIES Neoantigen-based NEON Products PLATFORM Adjuvant & metastatic Enhance efficacy in combination with checkpoint inhibitors Evaluate in checkpointunresponsive indications Later line metastatic Broaden into solid tumors Checkpoint-unresponsive indications 9

10 NEON THERAPEUTICS Our Differentiated Approach Leveraging Leading Neoantigen Platform Neoantigens Neon s core focus RECON Bioinformatics Engine Deep learning neoantigen predictor trained on mono-allelic mass spec data Patient data feedback loop further improves predictions Class II predictor coming online in 2019 NEO-STIM Proprietary, high-throughput T cell induction protocol Primes, activates and expands neoantigen-reactive T cells Peptide-based immunogen design Immune Monitoring Safe, immunogenic and scalable Neon s proprietary immunogen design can generate over 10-fold improvement in epitope immunogenicity Large combinatorial class I tetramer library for precise immunogenicity readouts Serial pre- and post-treatment apheresis & tumor biopsies Neoantigen-specific T cell functional & cytotoxicity assays 10

11 Emulating Neoantigen Biology In Silico Neoantigen Biology Image courtesy of the Broad Institute RECON 1 2 Ensemble of mutation callers RNA quantification & mutation validation Peptide processing predictor 5 Mass spectrometry-based single allele algorithms Class I Class II Validation using expression data from tumors Immunogenicity predictors using: in vivo immune responses (vaccine responses, epitope spread) and in vitro assays of T cell response 11

12 Personal Neoantigen Therapies Individual therapies targeting a patient s specific set of tumor neoantigens GMP Release Tumor Sample & Processing DNA & RNA Sequencing Bioinformatics Personal Peptide Manufacturing NEO-PV-01 Personal Neoantigen Vaccine Patient Patient s Peripheral Blood T cells & Monocytes Ex vivo Co-culture & Expansion NEO-PTC-01 Personal Neoantigen T Cell Therapy 12

13 Targeting Neoantigens Across Three Programs RESEARCH & PRECLINICAL DEVELOPMENT PHASE 1 LATER STAGE C ATALY S T S NEO-PV-01 Personal neoantigen vaccine NT-001: αpd-1 (Opdivo) Combo Melanoma, NSCLC, Bladder Cancer NT-002: αpd-1 (Keytruda) + Chemo Combo NSCLC 52-Week Data 1H:19 52-Week Data 2H:19 NT-003: αpd-1 + acd40 / αctla4 Combo Melanoma Immune Data 1H:20 NT-004: Trial in earlier disease setting NEO-PTC-01 Personal neoantigen T cell therapy Phase 1 Trial in solid tumor setting File CTA in Europe 1H:19 TARGET DISCOVERY TARGET VALIDATION PRECLINICAL DEVELOPMENT PHASE 1 LATER STAGE C ATALY S T S NEO-SV-01 Precision neoantigen vaccine Phase 1 Trial in breast cancer File First IND 1H:19 13

14 NEO-PV-01: Personal neoantigen vaccine 14

15 NEO-PV-01: Clinical Development Strategy Multiple exploratory clinical trials to inform a clear path to registration Establish safety & immune activity NT-001 NEO-PV-01 + nivolumab (αpd-1) Improve tumor microenvironment NT-002 NEO-PV-01 + pembrolizumab (αpd-1) + chemo Improve magnitude & quality of immune responses NT-003 NEO-PV-01 + acd40 or αctla4 Evaluate single agent activity NT-004 NEO-PV-01 Multiple Indications Adjuvant, Metastatic Metastatic Melanoma, NSCLC and Bladder Cancer 1st Line Metastatic NSCLC Metastatic Melanoma combinations Earlier disease setting 15

16 What Would You Look For in an Ideal Neoantigen Vaccine? Evaluating neoantigen T cell responses to determine: 1 Does NEO-PV-01 induce peripheral immune responses? 2 Do vaccine-induced T cells infiltrate the tumor? 3 Are the vaccine-induced T cells functional? 4 Do vaccine-induced T cells induce tumor cell killing? 5 Is there a correlation between immune response and clinical outcome? 16

17 NT-001: Study Design and Overview NEO-PV-01 + Nivolumab in αpd-1/pd-l1 naïve subjects 31 August

18 NT-001: Patient Demographics 31 August

19 NEO-PV-01 Safety Profile No vaccine treatment discontinuation due to adverse events (AEs) - Includes top 5 most frequently occurring AEs that are likely or possibly treatment related - Treated with nivolumab monotherapy = 80 patients - Treated with NEO-PV-01 + nivolumab = 54 patients 31 August

20 Vaccine-Induced Immunity in All 3 Tumors Types 1 Does NEO-PV-01 vaccine induce peripheral immune responses? 100% of patients exhibit ex vivo responses via IFN-γ ELISpot 87% of NEO-PV-01 peptides tested are mutant-specific Durable immune responses seen in 4 out of 6 patients assessed at Week 52 ESMO 2018 Presentation # 1127O (Ott, et al) 20

21 Vaccine-induced Neoantigen-specific TCRs Traced from Periphery to Tumor 2 Do vaccine-induced T cells infiltrate the tumor? RICTOR mutant neoantigen from melanoma patient M1 Melanoma patient with no prior therapy for metastatic disease with M1c disease Continues on study with stable disease for > 70 weeks Workflow TCR3 found in both periphery & tumor Tumor Sample Peripheral Sample Tumor biopsy Bulk CD3β Sequencing Comparison of TCRβ Repertoires RICTOR mutant (α/b) TCR 3 TCR 2 TCR 1 1 of 3 RICTOR TCRs found in periphery also found in tumor # of reads (normalized) TCR 1 TCR 2 TCR 3 Pretreatment TCR 1 TCR 2 TCR 3 Nivo monotherapy TCR 1 TCR 2 NEO-PV-01 + Nivo TCR 3 Tetramer+ ex vivo sorted Single cell RNA Matching TCR against mutant RICTOR neoepitope found in analysis comparing samples from periphery and tumor ESMO 2018 Presentation # 1127O (Ott, et al) SITC 2018 Neon Abstract #: Oral-07 21

22 Vaccine-induced TCR Found in the Tumor is Functional 3 Are vaccine-induced T cells functional? RICTOR mutant TCR from melanoma patient M1 Neoantigen-TCR in the Tumor M 1 T C R 3 ( J u r k a t ) + A W T M 1 T C R 3 ( J u r k a t ) + A B 5 1 : 0 1 J u r k a t + A W T I L - 2 ( p g / m l ) P e p t i d e C o n c e n t r a t i o n u M TCR3 expressed in Jurkat cells is functional, expressing IL-2 in presence of neoantigen epitope SITC 2018 Oral Presentation Hu-Lieskovan 22

23 Epitope Spread in 8 out of 10 Patients Tested 4 Do vaccine-induced T cells induce tumor cell killing? Mechanism: Vaccine-induced T cells recognize and kill tumor leading to tumor cell lysis, releasing new neoantigens which are taken up by dendritic cells and prime new T cells which kill additional tumor cells in a catalytic cycle 23

24 Melanoma: Tumor Burden Changes During Therapy Per Protocol Set (n = 16) % Change from Baseline Post-vaccination response Observed response > On study > Continued nivo Disease stabilization post-progression Prevaccination Postvaccination Totals PR 50.0% (8/16) 37.5% (3/8) 68.8% (11/16) CR 0% 6.3% (1/16) 6.3% (1/16) Continued Nivolumab Treatment* Discontinuation rate prior to week % (12/16) 21.4% (3/14) Weeks August % of patients had prior systemic therapy for metastatic disease 1 out of 4 patients with post-vaccine responses had prior systemic therapy for metastatic disease with patient M9 receiving 3 lines of prior treatment * On study or continuing nivolumab treatment as of recent correspondence 24

25 NSCLC: Tumor Burden Changes During Therapy Per Protocol Set (n = 11) % Change from Baseline Post-vaccination response Observed response > On study > Continued nivo Continued Nivolumab Treatment* Prevaccination Postvaccination Totals PR 27.2% (3/11) 25.0% (2/8) 45.5% (5/11) CR 0% 0% 0% (0/11) 63.6% (7/11) Weeks z 31 August % of NSCLC patients had prior systemic therapy for metastatic disease prior to enrollment 2 out of 2 patients with post-vaccine responses had one prior systemic therapy * On study or continuing nivolumab treatment as of recent correspondence 25

26 Bladder Cancer: Tumor Burden Changes During Therapy Per Protocol Set (n = 7) % Change from Baseline Complete regression in 2/2 target and 4/5 non-target lesions > On study > Continued nivo Continued Nivolumab Treatment* Prevaccination Postvaccination 85.7% (6/7) Totals PR 28.6% (2/7) 0% (0/5) 28.6% (2/7) CR 0% 0% 0% Weeks August 2018 * On study or continuing nivolumab treatment as of recent correspondence 71.4% of bladder cancers had prior systemic therapy before enrollment 26

27 Tumor Responses Post-Vaccination Changes in tumor measurements at week 12 vs. best response post-vaccination % Change from Pre-Vaccination Increase from Pre-Vaccination Decrease from Pre-Vaccination Melanoma NSCLC Bladder Continuing treatment Post-vaccine response Patients 31 August

28 NT-001: Immune Evaluation of NEO-PV-01 Mechanism of Action Evaluating neoantigen T cell responses to determine: 1 Does NEO-PV-01 induce peripheral immune responses? 2 Do vaccine-induced T cells infiltrate to the tumor? 3 Are the vaccine-induced T cells functional? 4 Do vaccine-induced T cells induce tumor cell killing? 5 Is there a correlation between immune response and clinical outcome? Full analysis planned for week 52 data 28

29 NEO-PTC-01: Personal neoantigen T cell therapy 29

30 Current State of the Art in T Cell Therapies SUCCESSES CHALLENGES CAR-T Approved for B cell cancers Potent with high response rates Single target approach Toxicity TCR-Based Cell Therapy Evidence of limited solid tumor activity Difficulty finding potent TCRs against tumor-associated antigens On-target, off-tumor toxicity TIL Therapy Case studies showing clinical effect in solid tumors Data limited to restricted group of patients Unknown clinical durability 30

31 NEO-PTC-01 Designed as Optimal T Cell Therapy Optimal T Cell Product Profile NEO-PTC-01 TUMOR SPECIFIC TARGETS Multiple neoantigen targets RECON enables personal target identification & selection BROAD IMMUNOGENICITY NEO-STIM leads to multiple pre-existing & de novo responses Reduced risk of immune escape IN VIVO EXPANSION OF CYTOTOXIC T CELLS Non-engineered T cells Starting material: peripheral blood mononuclear cells (PBMCs) 31

32 NEO-PTC-01 Personal Neoantigen T Cell Therapy Tumor Sample Sequencing Bioinformatics Peptide Production T Cell Manufacturing Patient NEO-PTC-01 Personal Neoantigen T Cell Therapy Leukapheresis 32

33 New Data on NEO-STIM Process Presented at SITC 2018 SITC Poster #P169 Proof of feasibility in patient material Multiple CD8 + and CD4 + T cell populations induced in each patient sample Highly functional induced T cells, specific for mutant neoantigens In vitro demonstration of tumor cell killing Reproducible NEO-STIM results across multiple patient samples 33

34 NEO-STIM Induces and Expands Multiple Neoantigen T Cell Populations Data from a single melanoma patient sample Expansion of Memory Response Induction of de novo Response Starting PBMCs Post NEO-STIM Starting PBMCs Post NEO-STIM Memory Response 4.5% of CD % of CD8 + de novo Response 1 0% of CD % of CD8 + pmhc Multimer A pmhc Multimer B 16-fold increase post NEO-STIM de novo Response 2 0% of CD % of CD8 + - NEO-STIM also induced three neoantigen CD4 + T cell populations in this patient sample - Specificity of mutant over wild-type epitope observed 34

35 NEO-STIM Induced T Cells are Highly Functional Data from a single melanoma patient sample Control Neoantigenactivated NEO-STIM induced T cells demonstrate cytokine release (IFNγ and TNFα) and degranulation (CD107a) upon activation 3 markers: IFNγ + TNFα + CD107a 2 markers observed 1 marker observed No activation markers CD8 + memory response CD8 + de novo response CD4 + de novo response 35

36 NEO-STIM Induced CD8 + T Cells can Kill Tumor Cells Expressing the Target Neoantigen Data from a single melanoma patient sample, CD8 + memory response Cytotoxic Marker CD107a on Induced Neoantigen T Cells Upregulation of Active Caspase-3 on Target Tumor Cells % C D 8 + C D a p< **** % L i v e + C a s p< Control Wild-type transduced Control Neoantigentransduced Neoantigentransduced Wild-type transduced Target tumor cell line Target tumor cell line 36

37 NEO-PTC-01 Development Plan NEO-STIM Optimization Clinical & GMP Readiness Clinical Development Completed initial process development of NEO-STIM in collaboration with Netherlands Cancer Institute (NKI) Successful scientific advice meeting with Dutch Health Authority in 2017 Finalizing GMP process development Broad clinical opportunity across indications, initial focus on solid tumors Planning first-in-human trial with CTA filing 1H

38 Vaccines T Cell Therapies 38

39 Precision Approach to Neoantigens Precision therapies targeting select tumor neoantigens shared across patient populations and tumor types SUITE OF PRODUCTS/MODALITIES Vaccines Patient Population Genomic Panel or Circulating Tumor DNA Assay Mutationpositive Patient TCR-T Cell Therapies 39

40 NEO-SV-01: Breast Neoantigen Vaccine Target Patient Population: Subset of ER + Breast CD8 + T CELL INDUCTIONS 1500 g IFNγ Sample 1 IFNg (pg/ml) Sam ple 1 Sam ple 2 CD107a %CD107a + /CD Adjuvant or metastatic patients Patient selection via gene panel No HLA restriction Pre-manufactured vaccine Proprietary set of peptide immunogens + adjuvant IND filing 1H Sam ple 1 Sam ple 2 Mutation-positive cell line Mutation-negative cell line CD4 + T CELL INDUCTIONS 40

41 Multiple TCR-T Cell Therapies Targeting Shared Neoantigens SHARED NEOANTIGEN TARGETS SHARED NEOANTIGEN TCR ISOLATION TCR-T PRODUCT DEVELOPMENT Multiple shared neoantigen targets across solid & heme Oncogenic drivers or resistance mutations Confirmed presentation of neoantigen by mass spec Isolation of libraries of potent TCRs from natural repertoire of multiple healthy donors No TCR maturation required TCR validation: specificity, functional avidity and cytotoxicity Initial TCR candidates for multiple targets Attractive target clinical populations Exploring partnerships to accelerate 41

42 Corporate 42

43 Targeting Neoantigens Across Three Programs RESEARCH & PRECLINICAL DEVELOPMENT PHASE 1 LATER STAGE C ATALY S T S NEO-PV-01 Personal neoantigen vaccine NT-001: αpd-1 (Opdivo) Combo Melanoma, NSCLC, Bladder Cancer NT-002: αpd-1 (Keytruda) + Chemo Combo NSCLC 52-Week Data 1H:19 52-Week Data 2H:19 NT-003: αpd-1 + acd40 / αctla4 Combo Melanoma Trial Initiation 2H:18 NT-004: Trial in earlier disease setting NEO-PTC-01 Personal neoantigen T cell therapy Phase 1 Trial in solid tumor setting File CTA in Europe 1H:19 TARGET DISCOVERY TARGET VALIDATION PRECLINICAL DEVELOPMENT PHASE 1 LATER STAGE C ATALY S T S NEO-SV-01 Precision neoantigen vaccine Phase 1 Trial in breast cancer File First IND 1H:19 43

44 Conclusion Leading Neoantigen Platform Multiple Therapeutic Modalities Pioneering Clinical Programs Well Capitalized Through Multiple Catalysts 44

45 Appendix I 45

46 RECON S MONOALLELIC PLATFORM Neon s Approach Greatly Enhances Presentation Prediction Platform Foundation Neon s growing proteomic database has generated data on >1.2 million HLA bound peptides Achieved >90% population coverage for MHC Class I PPV > 50% and exceeds netmhcpan by >10x when using a recall-based measurement of performance Enhanced understanding of antigen processing Clinical validation with immunogenicity and epitope spread Significant and expanding progress on Class II alleles 46

47 RECON IS REFINED BY CLINICAL DATA Neon Is Generating Significant Clinical Immune Data Broad Immunogenicity of Vaccinated Peptides >1000 vaccinated peptides Out of >250 peptides screened, 31% CD8 + responses & 49% CD4 + responses Additional Data Sources for Immunogenicity High throughput in vitro immunogenicity assay Neoantigen-specific TCR analysis in tumor and periphery Continued analysis of epitope spread in patients Pretreatment Nivolumab NEO-PV-01 + Nivolumab Immune data generated in the clinic is being used to further refine the peptide selection process 47

48 Proprietary Peptide Immunogen Design The Rationale for Peptides Intelligent Design Approaches The natural form of immunogens Fully synthetic chemistry Poly-IC/LC as potent adjuvant Processed into both Class I and II epitopes Proprietary design for optimal processing, over 1 log increase in MHC presentation Clinical & Process Validation 100% of patients generating ex vivo immune responses Immune responses observed out to 52 weeks 100% manufacturing success with >2,000 GMP peptides made 48

49 Appendix II 49

50 S p o t F o r m in g C e lls / 1 x 1 0 IFNγ spot forming cells /1*10 6 PBMCs Spot Form ing C ells/1 x 10 6 PBMCs P B M C s S p o t F o r m in g C e lls / 1 x Vaccination with NEO-PV-01 leads to Epitope Spreading in Patient M1 4 Do vaccine-induced T cells induce tumor cell killing? Patient M1: IFNγ ELISpot to non-vaccinating neoantigens Responses to Neoantigen Pools Responses to Neoantigens P B M C s P o o l 1 P o o l 2 P o o l 3 P o o l 4 D M S O N e o a n t i g e n p e p t i d e P o o l 1 Pre-treatment Nivo monotherapy NEO-PV-01 + nivolumab DYNC1H1 PCM1 PPAP2B QARS ZMPSTE24 (Background subtracted) Ex vivo S tim ulated C o n c e n t r a t i o n o f i n d i v i d u a l p e p t i d e s ( u M ) Of the 15 additional neoantigens tested, Patient M1 showed responses to 5 neoantigens 50

51 6 Case Study: Metastatic Melanoma Patient M2 5 Is there a correlation between immune response and clinical outcome? 67y male with stage M1c melanoma at enrollment No prior systemic therapy NEO-PV-01 Induces Neoantigen-Specific CD8 T cells IFNγ ELISpot Assay Tetramer and Phenotypic analysis Effector and Memory Phenotype 0% 0% P B M C s IF N γ S p o t F o r m in g C e lls / IM 2 5 IM 2 0 IM 2 3 IM 1 3 IM 2 7 IM 1 5 IM 2 2 IM 1 9 IM 0 5 IM 1 6 IM 2 1 IM 0 4 IM 2 5 IM 2 0 IM 2 3 IM 1 3 IM 2 7 IM 1 5 IM 2 2 IM 1 9 IM 0 5 I M 1 6 IM 2 1 IM 0 4 IM 2 5 IM 2 0 IM 2 3 IM 1 3 IM 2 7 IM 1 5 IM 2 2 IM 1 9 I M 0 5 I M 1 6 I M 2 1 I M 0 4 P r e - t r e a t m e n t N i v o l u m a b N i v o l u m a b + N E O - P V of the 18 vaccinated peptides generated a CD4 and CD8 response after 5 day neoantigen exposure. PE Tetramer APC Tetramer MLLT6 (IM04) Neoantigen 0.03 % CD45RA Mean Fluorescence Intensity E EM 78% CD107a CTLA4 CD62L Bulk CD8 T cells Tetramer+ T cells CD25 HLA-DR N CM 22% Cytolytic and Activation markers Neoantigen specific CD8 T cells express effector memory and central memory markers and have cytolytic phenotype. PD -1 51

52 Case Study: Metastatic Melanoma Patient M2 5 Is there a correlation between immune response and clinical outcome? Immune responses and epitope spread are durable and detected at 52 weeks Patient showed complete response at week 66 IFN γ Spot Form ing Cells/1 x 10 6 PBM Cs IM 23 IM August

53 Case Study: Metastatic NSCLC Patient L1 5 Is there a correlation between immune response and clinical outcome? 63y male diagnosed with NSCLC Front-line treatment with chemotherapy Lesions detected in lung, adrenal gland, mediastinum and bone at enrollment % Change from Baseline Vaccination Partial Response Weeks Patient had a partial response at week August of the 11 immunizing peptides generated a CD4 response Immune responses were durable and detected at 52 weeks post start of treatment 53

54 Case Study: Metastatic NSCLC Patient L1 NEO-PV-01 induces neoantigen-specific CD4 T cells 5 Is there a correlation between immune response and clinical outcome? Jurkat cells expressing TCR1-3 respond to neoantigen IHC analysis MHC Class II: Only pre- vaccine tumor is expresses MHC class II on surface Pre-Treatment 0% positive Nivolumab monotherapy Neoantigen specific CD4 T cells have cytolytic properties, express CD107a Single cell TCR sequencing of neoantigen specific CD4 T cells identified 3 dominant TCR clones CD4 TCRs are functional in a recombinant assay using autologous APCs 90% positive No accessible tumor available for biopsy post-vaccine 54