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Tipping the balance in favor of the immune system to fight cancer Paul
Peter Tak, MD, PhD, FMedSci President and Chief Executive Officer Candel Therapeutics, Needham, MA 1
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risks and uncertainties that could affect our business are included under the caption "Risk Factors" in our most recent report filed with the Securities and Exchange Commission. 1 2
Candel overview: Oncolytic viral immunotherapies Two clinical stage
investigational medicines and an innovative discovery platform CAN-3110 o Engineered, replication-competent herpes simplex virus with tumor-specificity o Ongoing phase 1 clinical trial in recurrent HGG o Potential for expansion of
indications CAN-2409 o Engineered, non-replicating adenoviral gene construct encoding HSV-thymidine kinase o Ongoing clinical trials in NSCLC, high-grade glioma (HGG), pancreatic cancer, and prostate cancer o Pipeline in a product
enLIGHTEN Discovery Platform based on HSV technology 3
CAN-3110: HSV "Nestin 34.5" construct Nestin expression in
tumor cells Nestin induces ICP34.5 expression, Promoter resulting in tumor-specific replication ICP34.5 CAN-3110 Virus expands in Nestin expressing tumor cells, causing oncolytic activity 4
Oncolytic HSV infection and CD8+ T cell infiltration after CAN-3110
treatment in patients with recurrent high-grade glioma 6 HSV1 antigen 6 weeks after injection of 1x10 pfu Infiltration by CD8+ cytotoxic T cells 6 1.79 x 10 copies of viral DNA/mg (tumor infiltrating lymphocytes) 5 2.97 x 10 copies of viral RNA
transcript (ICP22)/mg Post-treatment tissue (available in 18 patients) demonstrates persistence of HSV antigen and CD8+ T cell infiltrates T cell receptor repertoire, transcriptomics, and single cell RNA sequencing analyses are ongoing EA Chiocca et
al. Oral presentation. ASCO June 2021 5 New data: Q4 2022
Survival in ongoing phase 1b clinical trial after single dose of
CAN-3110 in recurrent high-grade glioma 100 N = 30 Median ove Me rall ds ia un r v O iv Sa : l:1 1 11.7 .7 m mo on nth thss Cutoff date: 21 April 2021 Expected median overall survival: <6-9 months 50 0 0 6 12 18 24 30 36 Months 6 Probability of
Single agent activity of CAN-3110 in recurrent HGG patient with abscopal
effect Secondary lesion Injected lesion Baseline Day 168 Day 0 Day 56 Day 111 Day 280 Black hole within tumor Reduction in contrast area Patient back to work image is injection site with no additional 6 10 PFU dose treatment Clinical effect on
injected tumor 56 YOM, IDH wild-type, MGMT partially methylated, right frontal mesial lesion initially treated with gross total resection, chemoradiation. Recurrences at two sites. and uninjected tumor 7
CAN-2409 treatment: Induction of CD8+ tumor-infiltrating lymphocytes in
prostate cancer and pancreatic cancer PROSTATE CANCER PH 1/2 STUDY PANCREATIC CANCER PH 1/2 STUDY Post-treatment with CAN-2409 Tumor infiltrating Pre-treatment lymphocytes in tissue and prodrug 140 120 Loss of glandular architecture 100 80 60
Necrosis N=7 40 P-value 0.0021 Typical glandular structures 20 Significant CD8 infiltration 0 Pre-GMCI Post-GMCI Pre-CAN-2409 Post-CAN-2409 21.6 Average Fold Increase Clinical evidence supports ongoing clinical trials of CAN-2409 in prostate cancer
and pancreatic cancer 8 Average count of CD8+ cells
Completed phase 2 trial of CAN-2409 shows consistently improved freedom
from failure rates in newly diagnosed, localized prostate cancer n= 64 99 203 31 92 127 255 102 21 177 184 103 10 Pathological complete response (pCR) observed in 93% of the biopsies available at 2yrs (37%-73% in control populations)
Low risk patients achieved PSA < 2ng/ml in 77% of CAN-2409 treated patients versus 58% in control populations Significant increase in activated CD8+ T cells compared to baseline (p=0.0003) Clinical evidence supports ongoing phase 3
clinical trial of CAN-2409 in combination with SoC as first line treatment Failure was measured from the start date of treatment until the date of treatment failure defined as clinical failure or biochemical failure, whichever first, according to
the Phoenix ASTRO consensus (Nadir +2) 9
Significant survival benefit after CAN-2409 treatment in HGG Compared
to contemporary controls fulfilling the same inclusion and exclusion criteria All patients: Prespecified subgroup: All high-grade glioma, glioblastoma with gross total resection All resection extent Median overall survival Median overall survival
CAN-2409 (n=48): 17.1 mo CAN-2409 (n=18): 25.1 mo SOC (n=134): 13.5 mo SOC (n=44): 16.3 mo HR (95%CI)= 0.72 (0.52-0.998) HR (95%CI)= 0.50 (0.29-0.86) p=0.0417 p=0.0120 Time (months) Time (months) 54% Relative improvement (8.8 mo median survival
benefit) Clinical evidence supports adaptive phase 3 clinical trial of CAN-2409 in high-grade glioma patients undergoing Gross Total Resection and standard of care chemoradiation (reviewed with FDA) Results have also been confirmed by comparison to
10 independent control cohort matched for known prognostic factors Survival rate (%) Survival rate (%)
Key achievements and future milestones Phase 2 CAN-2409 with ICI st in
NSCLC 1 patient dosed Phase 3 CAN-2409 in prostate cancer enrollment completed Phase 3 Phase 2 prostate cancer CAN-2409 blinded safety data prostate cancer Phase 2 CAN-2409 Phase 3 patient reported active surveillance intra-prostate delivery
tolerability prostate cancer Phase 2 CAN-2409 2023+ pancreatic cancer Phase 1 CAN-3110 HGG clinical activity data Phase 1 CAN-2409 with Opdivo 2022 HGG clinical activity data Phase 3 CAN-2409 HGG trial starts Phase 2 CAN-2409 with ICI NSCLC clinical
Leadership team with decades of experience in oncology, immunology, and
drug development Paul-Peter Tak, M.D., Ph.D., FMedSci President & Chief Executive Officer Francesca Barone, M.D., Ph.D. Chief Scientific Officer Nathan Caffo Chief Business Officer John Canepa Chief Financial Officer Christopher Matheny,
Pharm.D., Ph.D. Vice President, Development Leader Susan Stewart, J.D. Chief Regulatory Officer Seshu Tyagarajan, Ph.D., RAC Chief Technical and Development Officer 12
Research Advisory Board of premier thought leaders James Allison, Ph.D.
Roy Herbst, M.D., Ph.D. Chair of the Department of Immunology Chief of Medical Oncology MD Anderson Cancer Center Yale Cancer Center Director of the Parker Institute for Cancer Research 2018 Nobel Recipient Edward Benz, M.D. Philip Kantoff, M.D.
President and CEO Emeritus Former Chair, Department of Medicine Memorial Sloan Kettering Cancer Center Dana-Farber Cancer Institute Padmanee Sharma, M.D., Ph.D. Henry Brem, M.D. Director, Department of Neurosurgery Professor of Genitourinary Medical
Oncology and Professor of Neurosurgery Immunology Johns Hopkins University MD Anderson Cancer Center 13
Non-small cell lung cancer opportunity for CAN-2409 o Patients treated
with immune checkpoint Prevalence of NSCLC in the US* inhibitors often combined with chemotherapy st as 1 line treatment o Median overall survival 22 months rd nd 3 Line st 2 Line 1 Line o < 40% of patients survive > 30 months 21,990 47,920
75,160 o Opportunity to improve response by teaching the immune system how to recognize the cancer cells Target label for CAN-2409: Indicated as adjunct to standard-of-care immune checkpoint inhibitor treatment (+/- # chemotherapy) in stage III / IV
NSCLC patients not responding to first-line or later ICI treatment * Decision Resources Group 2020 # Market research and interviews with 13 KOLs (8 US and 5EU) Dec. 2020 14
First report from a phase 2 clinical trial of CAN-2409 in inadequate
responders to immune checkpoint inhibitors for stage III/IV NSCLC Daniel Sterman, MD Thomas and Suzanne Murphy Professor of Pulmonary and Critical Care Medicine, at the New York University Grossman School of Medicine, and Director of the Division of
Pulmonary, Critical Care, and Sleep Medicine, and Director of the Multidisciplinary Pulmonary Oncology Program at NYU Langone Health Conflict of interest disclosure: Nothing to disclose 15
CAN-2409: Mechanism of action 1. CAN-2409 locally 4. Local immunization
yields administered and oral prodrug systemic anti-tumor response Inflammatory Tumor Dendritic cell B-cell Valacyclovir mediators antigens Macrophage Fibroblast CAN-2409 Cytotoxic metabolite Thymidine kinase enzyme Valacyclovir CAN-2409 T-cell 2.
Localized cytolytic mechanism combined 3. CAN-2409 induces tumor with proinflammatory viral particles infiltrating lymphocytes
CAN-2409 teaches the immune system how to fight cancer in injected
tumor and uninjected metastases Decrease in uninjected lung metastases Uninjected lung metastases Virus injected flank tumor Mice receive one of four treatment regimens 1. PBS 2. Radiotherapy 3. CAN-2409 with prodrug 4. CAN-2409 with prodrug plus
radiotherapy Model of prostate cancer: RM-1 cells in C57BL/6 mice Chhikara M et al. Mol Ther 2001; 3:536-42 17
Response to CAN-2409 is dependent on 3000 CD8+ T cells and transferable
in mouse models of cancer 2500 140 Control vector 120 2000 + prodrug w/ CD8 mAb 100 1500 80 60 1000 Control vector CAN-2409 + prodrug 40 + prodrug 500 w/ CD8 mAb 20 CAN-2409 + prodrug prodrug 0 0 Control cells only Na ve CD8+ cells Control
vector CD8+ CAN-2409 CD8+ cells 0 5 10 15 20 25 30 cells Days vector CD8+ cells from cured' mice administered CAN-2409 Depletion of CD8+ cells eliminated effect protected na ve mice from tumor challenge Winn Assay: Lung cancer
model (TC-1) flank tumors Esophageal cancer model (AKR) flank tumors in C57Bl/6 mice (n = 5 per group) in C57Bl/6 mice (n = 8 per group) Predina JD et al. J Hematol Oncol 2012; 5:34 18 3 Tumor volume (mm ) 3 Tumor volume (mm )
Phase 1 mechanistic trial in resectable NSCLC: Safety and feasibility
of intratumoral administration of CAN-2409 Evidence of monotherapy activity both via biomarkers and clinical response CAN-2409 and valacyclovir Newly diagnosed Day 0 Day 1-15 Day 21 +6-8 weeks +6 months (one course) stage I-III Standard of care
Study specific suspected Oral CAN-2409 Planned surgery chemotherapy follow up valacyclovir 3+3 dose operable radiation escalation NSCLC Injected into tumor N=12 completing during SoC staging treatment and Tumor Tumor procedure sample sample
surgical resection (endobronchial or direct injection) PBMC and serum collected at multiple time points for immunological biomarkers No other therapy CAN-2409 dose levels: 11 11 12 2.5 x 10 , 5 x 10 , 1 x 10 VP Principal investigators: Dr S Singhal
(UPenn) and Dr S Albelda (UPenn) 19
CAN-2409 stimulates local and systemic CD8+ T-cell response in patients
with NSCLC Non-small cell lung cancer Ph 1 study (n=12) TISSUE PERIPHERAL BLOOD CD8 Ki67 CD8 Ki67 30 80 p<0.001 p=0.02 CD38 HLA-DR 60 CD38 HLA-DR 20 80 50 p=0.002 p=0.008 40 10 40 20 60 30 0 0 40 Pre Rx Post Rx Pre Rx Post Rx 20 20 CD38 HLA-DR 10
HLA-DR CD38 80 100 p=0.40 0 0 p=0.002 Pre Rx Post Rx Pre Rx Post Rx 80 60 60 40 PD1 CTLA-4 CTLA-4 PD1 40 20 80 40 p=0.004 p=0.043 20 0 0 60 30 Pre-Rx Post Rx Pre Rx Post Rx 40 20 PD1 PD1 CTLA-4 CTLA-4 100 80 p<0.001 p=0.002 20 10 80 60 0 0 60 Pre
Rx Post Rx Pre Rx Post Rx 40 40 20 20 0 0 Pre Rx Post Rx Pre Rx Post Rx Predina JD et al. Mol Ther 2020; 29:1-13 20 % of CD8 TILs expressing PD1 % of CD8 TILs expressing CD38 % CD8 of live tumor cells % of CD8 TILs expressing CTLA-4 % of CD8 TILs
expressing HLA-DR % of CD8 TILs expressing Ki67 % CD8's expressing PD1 % CD8's expressing CD38 % CD8's expressing CTLA-4 % CD8's expressing HLA-DR
Monotherapy activity of CAN-2409 in NSCLC 70 yr old male with a 14.8 cm
stage IIIA sarcomatoid carcinoma Day 22 Day 0 Tumor Dimensions: 100 x 34 x 75 mm Tumor Dimensions: 148 x 40 x 82 mm 12 10 vp dose Nearly 50% decrease in tumor volume* at 3 weeks after CAN-2409 monotherapy Predina JD et al. Mol Ther 2020; 29:1-13 21
Current, ongoing phase 2 clinical trial of CAN-2409 in combination with
ICI in stage III/IV NSCLC Cohort 1 Stable Disease (>18 wks ICI) Stage III/IV Primary Endpoints CAN-2409 and o Response by RECIST Criteria Non-resectable valacyclovir o Safety NSCLC with (2 courses) inadequate Cohort 2 Secondary Endpoints response
to ICI Progressive Disease (>18 wks ICI) o Overall survival with o Progression free survival standard of care: o Quality of life N=96 Anti-PD-1/PD-L1 +/- o Immunological biomarkers (32 per cohort) o Response by iRECIST and chemotherapy itRECIST
(Exploratory) Cohort 3 Refractory Disease (>9 wks ICI) ASCO 2022 Annual Meeting Abstract # 9037 Poster session June 6, 2022 8:00-11:00 CDT 22
Demographics 35 patients enrolled between October 2020 and April 2022