EX-99.1 2 cadl-ex99_1.htm EX-99.1

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Safety and survival outcomes in recurrent high-grade glioma patients treated with CAN-3110, a first-in-class ICP34.5 expressing oncolytic HSV1   Francesca Barone, MD, PhD Chief Scientific Officer, Candel Therapeutics, Inc. Exhibit 99.1


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CAN-3110 a novel oncolytic virus engineered for enhanced activity and safety HSV-1 engineered for immunogenic potency and specificity ICP34.5-null viruses have shown safety, but replicate poorly CAN-3110: ICP34.5 expression under control of Nestin promoter Nestin overexpressed in gliomas (and tumors outside of the brain) Improves replication  Provides tumor-specific oncolytic activity Designed for safety Disruption of ICP6 limits virus replication to dividing cells or cells with p16 tumor suppressor pathway defects Remains sensitive to anti-herpetic drugs Nestin provides tumor specificity


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CAN-3110 induces tumor cell death and reprograms the highly immunosuppressive microenvironment of HGG Cold tumor Highly immunosuppressive TME Cancer cell proliferation Hot tumor Inflamed TME Cancer cell necrosis Tumor cell death Release of tumor antigens Expansion of T cell repertoire Activation of local microenvironment


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Phase 1b clinical trial of CAN-3110 in recurrent high-grade glioma Primary Endpoints Safety Determine maximum tolerated dose Secondary Endpoints Immunological biomarkers MRI assessment of disease and progression free survival MRI alteration of permeability and flow at injection site Patients with recurrent high-grade glioma Lesions  ≥ 1.0 cm Dose escalation (Cohort I-IX) Single stereotactic injection of CAN-3110 3+3 dose escalation 1 x 106 to 1 x 1010 PFU in half-log increments 30 patients dosed Dose expansion (Cohort X) 1 x 109 PFU 11 patients dosed PI: Dr. E. Antonio Chiocca (Brigham & Women’s) Pre-Administration of Cytoxan +1 x 108 PFU 3 patients dosed +1 x 109 PFU 6 patients dosed Repeat Dosing (up to 6) +1 x 108 PFU x 6 doses +1 x 109 PFU x 6 doses 12 patients targeted Arm A Arm B NCT03152318 Arm C


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Patient demographics and baseline characteristics 41 unique patients were dosed; one patient was treated twice, in cohort IX and X A total of 50 unique patients * See below   Arm A  (n=41*) Arm B (n=9) Total  (n=50*) Age, Median (range)   54 years (27 - 74) 54 years (41 - 70) 55 years (27 - 74) Sex, n (%)       Female 21 (51%) 3 (33%) 24 (48%)   Male 20 (49%) 6 (67%) 26 (52%) Race, n (%)         White 38 (93%) 8 (89%) 46 (92%)   Black or African American 1 (2%) 0 (0%) 1 (2%)   Asian 2 (5%) 1 (11%) 3 (6%) Ethnicity, n (%)         Non-Hispanic 40 (98%) 8 (89%) 48 (96%)   Hispanic or Latino 0 (0%) 1 (11%) 1 (2%)   Unknown 1 (2%) 0 (0%) 1 (2%) IDH Status, n (%)           Wild-Type 32 (78%) 7 (78%) 39 (78%)   Mutant 9 (18%) 2 (22%) 11 (25%) MGMT Status, n (%)         Methylated 16 (39%) 2 (22%) 18 (36%)   Unmethylated 23 (56%) 7 (78%) 30 (60%)   Unknown 2 (5%) 0 (0%) 2 (4%) Grade, n (%)         III 7 (17%) 0 (0%) 7 (14%)   IV 34 (83%) 9 (100%) 43 (86%) KPS Score, Median (range)   90 (70 - 100) 90 (80 - 100) 90 (70 - 100)


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CAN-3110 related SAEs in rHGG (arms A and B) Cohort (arm) Number of treated patients Dose Level (PFU) Number of patients with DLT Number of patients with related SAE Case # Time (days) 1 (A) 3 1x106 0 0 NA NA 2 (A) 3 3x106 0 0 NA NA 3 (A) 3 1x107 0 0 NA NA 4 (A) 3 3x107 0 0 NA NA 5 (A), 1 (B) 6 1x108 0 0 NA NA 6 (A) 3 3x108 0 0 NA NA 7 (A), 10 (A), 2 (B) 21 1x109 0 1 046(IDHmut) 2 8 (A) 3 3x109 0 1 033(IDHmut) 16 9 (A) 6 1x1010 0 0 NA NA TOTAL 50* 0 2 Time range (days) 2 to 16 DLT: dose limiting toxicity, SAE: serious adverse event * Total includes one patient who received two injections, one in cohort 9 (A) and one in cohort 10 (A) As of cutoff date  25 Apr 2023


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Arm  A (n=41) n (%) General disorders and administration site conditions Fever 3 (7%) Musculoskeletal and connective tissue disorders              Muscle weakness 3 (7%) Nervous system disorders Seizure 3 (7%) Safety summary: related adverse events* (AEs) in rHGG Arm B (n=9) n (%) Nervous system disorders Edema Cerebral 1 (11%) Hemianopia 1 (11%) Hypoesthesia 1 (11%) * events manifesting in ≥5% of patients


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No patients experienced a DLT in Cohorts I-X All patients (n=41) experienced at least 1 AE 27% of patients (n=11) experienced at least 1 related AE 59% of patients (n=24) experienced at least 1 serious AE Most Serious AEs: Edema Cerebral (n=8 [20%]) and Seizure (n=5 [12%]) 5% of patients (n=2) experienced at least 1 serious related AE 001-033: Grade 3 – Seizure, Cerebral hematoma 001-046: Grade 2 - Seizure, muscle weakness , facial paresis Most *TEAEs were Grade 1-3 Most common Grade 3 AEs include Edema Cerebral (n=8 [20%]), Seizure (n=5 [12%]) and Muscle weakness (n=5 [12%]). One patient experienced a grade 5 cardiac arrest, non-related No grade 4 AEs All patients (n=9) experienced at least 1 AE 11% of patients (n=1) experienced at least 1 related AE 001-060: Grade 2 – Edema cerebral, left leg numbness, left visual field defect 22% of patients (n=2) experienced at least 1 serious AE 001-061: Grade 3 – Edema cerebral, muscle weakness  001-065: Grade 3 – Cerebrospinal fluid leakage, left hemiparesis, pseudo-meningocele and muscle weakness No patient (n=0) experienced a serious related AE All *TEAEs were grade 1-3 Most common Grade 3 AEs include Muscle Weakness  (n=2 [22%]) No grade 4 or 5 AEs Arm A (n=41*) Safety summary: adverse events in rHGG Arm B (n=9) * 41 unique patients were dosed; 00030 was treated twice, Cohort IX and X * Treatment Emergent Adverse Events (TEAEs)


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Encouraging overall survival in rHGG after single injection (arm A) N = 30  Median overall survival: 11.8 months Cutoff date: 20 Apr 2023 Expected median overall survival: <6-9 months 41 unique patients were dosed; one patient was treated twice, in cohort IX and X A total of 50 unique patients


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Overall survival data rHGG arm B confirms data in arm A N = 9 patients pretreated with cyclophosphamide   Median overall survival: 12 months Cutoff date 20 Apr 2023 Expected median overall survival: <6-9 months


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Day 56 Reduction in contrast area with no additional treatment Day 111 Patient back to work Baseline Clinical effect on injected tumor and uninjected tumor Day 168 Day 280 Day 0 Black hole within tumor image is injection site 106 PFU dose 56 YOM, IDH wild-type, MGMT partially methylated, right frontal mesial lesion initially treated with GTR, chemoradiation. Recurrences at two sites. Monotherapy activity of CAN-3110 in rHGG (arm A)


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Durable response for 2Yrs after CAN-3110 in rHGG (arm A) Day -47 Tumor recurrence Day -30 2nd subtotal resection Day -262 Initial presentation Day -14 Rapid progression Day -259 Initial resection 61 YOF, IDH wild-type, MGMT methylated glioblastoma, right temporal lesion initially treated with surgery, chemoradiation and temozolomide CAN-3110 dose: 108 PFUs. Patient passed away as passenger in a motor vehicle accident on day 717. Day 91 Tumor recurrence with TIL Day 96 After resection, histology shows TILs Day 0 CAN-3110 Injection Day 630 No visible tumor Needle visible on MRI Initial lesion Tumor bed injection site


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Continued improvement for >12Mos after CAN-3110 monotherapy (arm B) Day 0 CAN-3110 injection Day 64 Day 106 Pre-op Day -4 52 YO RH WF, IDH mutant, MGMT methylated grade IV astrocytoma (left frontal, invading corpus callosum in a butterfly fashion and lobulating into lateral and third ventricle). Recurrent disease, 1Yr after original resection. Enrolled in arm B: Cytoxan (24 mg/kg; day -2) & CAN-3110. Since injection KPS remains between 90 and 100, pt. independent at home with family, without other therapies. Day 180 Day 350 Initial lesion CAN-3110 Injection cavity Stable disease Day 280 Reduction in enhancement with tumor involution Cytoxan (day-2) Progressive reduction in enhancement Increased enhancement


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Biomarker Analysis


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Persistent HSV antigen expression associated with CD8+ T cell infiltration after CAN-3110 treatment Patient A (6 weeks post-HSV 10e6 PFUs) HSV1 Ag Day 253 Preoperative Intraoperative injection Anti HSV CD8+ Recurrence Patient B (9 mos post-HSV 10e9 PFUs) 13/27 patients presented positive oHSV antigen in post-injection samples collected in a range of 24 to 801 days post treatment


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Injected lesion Uninjected lesion Uninjected lesion Pre-treatment Post-treatment* *8 Mos Persistent HSV antigen expression in uninjected lesion 8 Mos after CAN-3110 injection in multifocal rHGG HSV-1 Uninjected lesion


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P<0.0001 P<0.0001   P<0.0005 P<0.0001   21/29 tumors p =0.0016 24/29 tumors p <0.0001 14/29 tumors CD8 CD4 CD20 Increased infiltration by immune cells at the site of the tumor after CAN-3110 treatment in rHGG Post-injection necrotic tumor areas surrounded by T cells anti HSV H&E 3 x107 PFU d 24 1 x108 PFU d 91 3 x107 PFU d 140 # necrosis; * immune cell infiltrate # * # * # * * # H&E


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Changes in tumor microenvironment after CAN-3110 are associated with improved survival in rHGG 17 paired samples bioinformatic analyses by BostonGene, Inc.


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Changes in protein biomarkers in peripheral blood after CAN-3110 injection in rHGG From 96 protein panel biomarkers, 53 showed statistically significant changes compared to baseline at the 1st or 2nd time points after treatment; those include IL-6, PTN, MMP12, CCL19, CD40L


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T cell receptor (TCR) analysis interpretation tool Relationship between clonality and diversity/entropy


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Increases in T cell density, entropy, and clonality are observed in long survivors after CAN-3110 injection Short survivor CAN-3110 injection Long survivors


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Conclusions Treatment with CAN-3110 in rHGG is well tolerated with no dose-limiting toxicity observed Persistence of HSV antigen expression associated with tumor necrosis and increased immune cell infiltration after CAN-3110 injection in both injected and uninjected lesions Evidence of abscopal effect Increase in pro-inflammatory mediators after CAN-3110 injection in rHGG Immunological changes in the tumor microenvironment after CAN-3110 injection in rHGG are associated with improved survival Increases in T cell density, entropy, and clonality are observed in long survivors after CAN-3110 injection Next, we will evaluate the effects of repeat injections with CAN-3110, supported by the Break Through Cancer foundation


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Acknowledgements Alexander Ling Isaac H. Solomon Ana Montalvo Landivar Hiroshi Nakashima Andres Santos Nafisa Masud Patrick Wen Keith Leigon David Reardon Sengupta Soma E. A. Chiocca Andrea Manzanera Maria Lucia Silva Polanco Garrett Nichols Paul Peter Tak