Durable Responses Observed in Recurrent High Grade Glioma (rhgg) with Toca 511 & Toca FC Treatment

Durable Responses Observed in Recurrent High Grade Glioma (rhgg) with Toca 511 & Toca FC Treatment Cloughesy TF 1, Landolfi J 2, Vogelbaum MA 3, Ostertag D 4, Elder JB 5, Bloomfield S 2, Carter B 6, Chen CC 7, Kalkanis SN 8, Kesari S 9, Lai A 1, Lee IY 8, Liau LM 1, Mikkelsen T 10,11, Nghiemphu PL 1, Piccioni D 10, Accomando W 4, Diago O 4, Hogan D 4, Jolly DJ 4, Wood K 4, Gruber HE 4, Das A 4, Walbert T 8 1 University of California, Los Angeles, 2 JFK Medical Center, 3 Cleveland Clinic Foundation, 4 Tocagen Inc., 5 Ohio State University, 6 Massachusetts General Hospital, 7 University of Minnesota, 8 Henry Ford Hospital, 9 John Wayne Cancer Institute, 10 University of California, San Diego, 11 Ontario Brain Institute

Disclosure Financial relationships: Monteris, Consultant MRI Intervention, Consultant Tocagen, Consultant Varian, Honorarium 2

Toca 511 (vocimagene amiretrorepvec) Retroviral replicating vector that carries a prodrug activator enzyme Regulatory genes Structural RRV genes CD gene Regulatory genes Tumor selectivity and replication in cancers cells is driven by: Defects in the innate immune system of cancer cells Virus enters some normal cells, but is rapidly eliminated by innate and acquired immunity Virus spreads through tumor without triggering immune system Virus only infects dividing cells Optimized CD (cytosine deaminase) 5-FC (Toca FC) Antifungal Prodrug 5-FU Anticancer Drug 5-FU has a very short half-life with direct cell killing localized to cancer microenvironment RRV= Retroviral replicating vector 3

Toca 511 & Toca FC: Toca 511 spreads then converts Toca FC to 5-FU for tumor killing and immune activation Novel 5-FU delivery kills tumor cells and activates immune system against cancer STEP 1 - Toca 511 & CD CD CD Proposed MOA: Tumor killing and anticancer immune activation CD Tumor STEP 2 - Toca FC 5-FU 5-FU 5-FU 4 Brain and tumor samples from Tocagen clinical trial patients CD = cytosine deaminase (yeast) Toca FC = extended release 5-FC

Toca 511 & 5-FC Immune Activation MOA Publications Selected for Cover and Editorial Neuro-Oncology, Vol 19, Issue 7, July 2017 Complementary preclinical studies published in July issue of Neuro-Oncology Increased immune infiltrates in tumor Immune effects are T cell-dependent and correlate with depletion of immune-suppressive myeloid cells the immunological milieu induced by the Toca 511 and 5-FC treatment, resulting in elimination of immunosuppressive tumor stromal cells and activation of antitumor immunity conventional chemotherapy with systemic 5-FU also causes myelotoxicity and damages the immune system. In contrast, with retroviral prodrug activator gene therapy, 5-FU is locally generated directly within infected glioma cells, and the immune system remains intact. Okada and Thorne, Dept. of Neurological Surgery and Cancer Immunotherapy Program, University of California San Francisco Dept. of Cell Biology, University of Pittsburgh 5

Three phase 1 ascending dose trials* in recurrent high grade glioma setting evaluating delivery approaches (n=127) Resection Injection into cavity wall after removal of tumor Intratumoral Direct injection into tumor Intravenous Injection IV prior to resection and into cavity wall at resection NCT01470794 (n = 56) NCT01156584 (n = 54) NCT01985256 (n = 17) *All three trials finished enrollment 6

Toca 511 associated with a very low % of treatment-related AEs, across all Grades Adverse events related to Toca 511 pooled across three phase 1 studies Treatment-Related Adverse Events Toca 511 n = 127 Grade 1/2 Grade 3* n (%) n (%) Any treatment-related event 32 (25.2) 9 (7.1) Treatment-related event in 3 patients Fatigue 14 (11.0) 1 (0.8) Headache 6 (4.7) 1 (0.8) Convulsion 6 (4.7) 0 Confusional state 5 (3.9) 0 Pyrexia 5 (3.9) 0 Nausea 4 (3.1) 0 Hemiparesis 3 (2.4) 0 Vasogenic cerebral edema 1 (0.8) 2 (1.6) Any treatment-related SAE 1 (0.8) 7 (5.5) Data cutoff 17 Apr 2017; excludes data from continuation study 7 Absence of vector insertion site clonality supports safety *No deaths considered related to Toca 511

Toca FC has very limited Grade 3 treatment-related toxicities Adverse events related to Toca FC pooled across three phase 1 studies Treatment-Related Adverse Events Toca FC n = 122 Grade 1/2 Grade 3* n (%) n (%) Patients with any treatment-related event 50 (41.0) 4 (3.3) Treatment-related event in 3 patients Fatigue 27 (22.1) 0 Diarrhea 16 (13.1) 1 (0.8) Nausea 12 (9.8) 0 Decreased appetite 6 (4.9) 0 Vomiting 4 (3.3) 0 Rash 3 (2.5) 0 Patient with any treatment-related serious adverse event 0 2 (1.6) Adverse Events Leading to Discontinuation 1 (0.8) 2 (1.6) Data cutoff 17 Apr 2017; excludes data from continuation study 8 *No deaths considered related to Toca FC

Toca 511 & Toca FC have a favorable safety profile compared to a historical control Toca 511 & Toca FC n = 27* Grade 2 Grade 3 to 4 n (%) n (%) Nonhematologic toxicity Fatigue 2 (7.4%) 0 Nausea 1 (3.7%) 0 Edema peripheral 0 0 Alanine aminotransferase increased 0 0 Hematologic toxicity Thrombocytopenia 0 0 Platelet count decreased 0 0 Neutropenia 0 0 Neutrophil count decreased 0 0 Leukopenia 0 0 White blood cell count decreased 0 0 Anemia 0 0 Hemoglobin decreased 0 0 Lympopenia 0 0 Lomustine n = 84 Grade 2 Grade 3 to 4 n (%) n (%) Nonhematologic toxicity Fatigue 4 (4.8%) 0 Nausea 2 (2.4%) 0 Edema peripheral 2 (2.4%) 0 Alanine aminotransferase increased 1 (1.2%) 1 (1.2%) Hematologic toxicity Thrombocytopenia 9 (10.7%) 20 (23.8%) Platelet count decreased 0 1 (1.2%) Neutropenia 4 (4.8%) 11 (13.1%) Neutrophil count decreased 0 6 (7.1%) Leukopenia 3 (3.6%) 4 (4.8%) White blood cell count decreased 1 (1.2%) 2 (2.4%) Anemia 1 (1.2%) 2 (2.4%) Hemoglobin decreased 2 (2.4%) 0 Lympopenia 2 (2.4%) 0 Patient Group Comparison Database enzastaurin study 1 (nonsurgical) Reasonably contemporaneous - Tocagen trial: 2012-2015 - Lomustine trial: 2006-2010 Demographics comparable - Tocagen: More KPS 90-100 - Lomustine: More 1 st recurrences Fewer on steroids 1 Wick et al, JCO 2010 *patients with GBM, 1 st and 2 nd recurrences; Adapted from Cloughesy et al, STM, 2016 9

Three phase 1 ascending dose trials* in recurrent high grade glioma setting evaluating delivery approaches (n=127) Resection Injection into cavity wall after removal of tumor Intratumoral Direct injection into tumor Intravenous Injection IV prior to resection and into cavity wall at resection NCT01470794 (n = 56) NCT01156584 (n = 54) NCT01985256 (n = 17) *All three trials finished enrollment 10

Phase 1 ascending dose trial of safety & tolerability of Toca 511 & Toca FC in rhgg Toca 511 administered into the resection cavity wall Eligibility GBM or AA Planned resection 80% 18-75 yrs old Single or contiguous tumor KPS 70 Adequate lab values No prior bevacizumab for recurrence Tumor 5 cm S U R G E R Y Toca 511 once From 1.4 X 10 7 to 4.8 X 10 9 TU (half-log increases) Multi-center Adaptive 3+3 design Cyclic Toca FC From 135 to 220 mg/kg/day Dose Escalation Objective: Safety, tolerability, and MTD Adapted from M.A. Vogelbaum, MD PhD, SNO, Nov. 21 st, 2015 11

Basic demographics show predominantly GBM patients 1 includes gliosarcoma 2 Higher doses (cohorts 4-7a) and meet P2/3 entry criteria of 1 st and 2 nd recurrence, no prior Avastin in raa or rgbm, tumor not > 5cm 12 Population All Patients N = 56 Higher Doses and P2/3 Entry Criteria Subset 2 N=23 Median Age (range) 56 (24-75) 54.8 (24-70) n (%) n (%) Male 43 (77) 20 (87) Karnofsky Performance Score 70-80 90-100 Initial Tumor Histology GBM 1 Anaplastic Astrocytoma Anaplastic Oligodendroglioma Other gliomas Number of Recurrences Including Current 1 2 3 or greater 17 (30) 39 (70) 46 (82) 6 (11) 1 (2) 3 (5) 28 (50) 13 (23) 15 (27) 5 (22) 18 (78) 19 (83) 4 (17) 0 0 19 (83) 4 (17) 0 Data cutoff date August 15 th, 2017

All responders are now in complete response and alive All responses are in higher dose cohort and durable Response Category 1 Durable response rate (CR or PR 24 weeks) Median duration of durable response All Efficacy Evaluable Patients N=53 2, n (%) Higher Doses and P2/3 Entry Criteria Subset 3 N=23, n (%) 6 (11.3); All CR 4 5 (21.7); All CR 5 35.1+ months (9.2-44.9) 35.7+ months (14.1-44.9) Stable disease 10 (18.9) 5 (21.7) Compares favorably with lomustine*: Overall response - 4.3% Duration of response - 2.8-9.6 months * Wick, JCO 2010 Progressive disease 37 (69.8) 13 (56.6) Clinical Benefit Rate (CR, PR, and SD at 8 weeks) 16 (30.2) 10 (43.5) 13 1 Includes MRI by independent radiology review and clinical data 2 of 56 safety evaluable patients, 53 patients who received Toca 511 & Toca FC are efficacy evaluable and of these 2 were not evaluable for response 3 Higher doses (cohorts 4-7a) and meet P2/3 entry criteria of 1 st and 2 nd recurrence, no prior Avastin in raa or rgbm, tumor not > 5cm 4 Includes 4 IDH wildtype and 2 IDH mutant patients 5 Two patients converted from PR to CR status since last data cutoff Data cutoff date August 15 th, 2017

A positive association of durable response with overall survival Best response & survival post progression rgbm or raa at 1 st /2 nd recurrence, no prior Avastin, 5 cm, Higher Dose Cohorts 019 017 034 032 033 041 037 026 031 046 028 036 043 014 044 025 040 035 039 021 042 045 018 mos lomustine = 8.4 months (rgbm) * GBM, IDH1 wt * PD SD PR CR AA, IDH1 mt AA, IDH1 mt GBM, NA * * * Alive at last contact Responses occurred gradually over time ~ 6-19 months, consistent with immunologic response All Responders alive 33.8+ to 52.2 + months, so far All CRs confirmed Median duration of response is 35.7+ months * * GBM, IDH1 wt GBM, IDH1 wt mos Toca 511 & Toca FC* = 14.4 months 0 10 20 30 40 50 60 *Higher doses (cohorts 4-7a) and meet P2/3 entry criteria Time on study in Months 14 Data as of August 28 th 2017

Encouraging landmark survival for patients received Toca 511 & Toca FC Landmark Survival % All Efficacy Evaluable Patients N = 53 Higher Doses and P2/3 Entry Criteria Subset 1 N=23 OS-12 month 49.1 65.2 OS-24 month 24.5 34.8 OS-36 month 13.4 26.1 1 Higher doses (cohorts 4-7a) and meet P2/3 entry criteria of 1 st and 2 nd recurrence, no prior Avastin in raa or rgbm, tumor not > 5cm Data as of August 15 th 2017 15

Complete response in a patient with progressive GBM, IDH1 wt PR at 6 months, CR at 48 months*, alive > 52 months *Independent Radiology Review, Macdonald criteria 16 Toca FC cycle is every 6 weeks

Conclusions Toca 511 & 5-FC activates durable T-cell mediated immune responses pre-clinically Treatment was well tolerated limited Grade 3 drug-related toxicities in three Ph1 studies (127 patients) Ph1 resection/injection study indicates: Prolonged survival relative to historical benchmarks In a subset (n=23) that mirrors Phase 3 study (Toca 5) population 5 complete responses (3 rgbm with IDH1 wt, 2 raa with IDH1 mt) are ongoing with median duration of response 35.7+ months Durable response rate may be a valuable end point for immunotherapeutics A positive association between durable response and overall survival Clinical activity and MOA data supported Breakthrough Therapy and PRIME designations Findings support ongoing Phase 3 randomized study (Toca 5) in patients with rhgg enrolling soon for patients with raa or rgbm 17

Thanks to all the patients, their families and caregivers who have supported this work. Financial support provided by 18