Intra-tumoral delivery of tavokinogene telseplasmid (pIL-12) by electroporation: immunomodulation in melanoma and triple negative breast cancer Sharron Gargosky PhD
Presentation Topics • Rationale of cytokine choice and electroporation delivery • Clinical data in metastatic melanoma • Clinical data in metastatic TNBC 2
• Plasmid IL-12 INN name: tavokinogene telseplasmid; Therapy and Terms aka “TAVO” • Device = OncoSec Medical System = OMS o The gene is human IL-12 cDNA, and is cloned into the bacterial plasmid pUMVC3. o IL-12 is a 70 kilodalton protein consisting of two subunits, 40 kD and 35 kD, stabilized by a disulfide bond. Innate and Systemic anti- Intratumoral Injection of IL-12 is ④ ⑤ ② ① ③ tumor immune cellular electroporation tavokinogene expressed & responses response delivers tavo telseplasmid secreted into the cells (tavo) 3 3
Prior approaches to cytokine delivery • Transient Exposure • Regression of treated lesions IT • No systemic effect • Sepsis-like side effects IV • 3-5% long-term remission • Intra cellular Accessible lesions • Tumor makes IL-12 Systemic disease Plasmid IL12 • 1 week exposure / tx TAVO 4
Why interleukin -12 (IL-12) tavokinogene telseplasmid 5
Agenda • Rationale of cytokine choice and Electroporation delivery • Clinical data in metastatic melanoma • Clinical data in metastatic TNBC 6
Clinical data in Metastatic Melanoma OMS-100 Phase 2 Repeat Dose: Abscopal tumor response and continued safety OMS-100 Phase 2 Repeat Dose Retrospective Analysis: Evidence of priming for anti-PD-1 response and continued safety OMS-102 Phase 2 Combination Study with Pembrolizumab: Evidence of efficacy in predicted anti-PD-1 non-responder population and continued safety 7
Phase 2 (OMS-I100): Metastatic Melanoma monotherapy tavo Regimen A Phase 2 open label, multicenter study of IT- IT-tavo-EP tavo-EP in metastatic melanoma Days 1, 5, 8 Dose and administration 90 days • Intratumoral injection of tavo (0.5 mg/mL) at a dose- volume of one-fourth the calculated lesion volume Regimen B Regimen A (part 1) IT-tavo-EP Days 1, 8, 15 • One cycle of treatment; additional cycles may be administered at 3-month intervals up to a max of 4 6 weeks total cycles • Tumor response evaluation: days 90, 180, and 270 Regimen C Regimens B and C (part 2) OR IT-tavo-EP Days 1, 5, 8 • Up to 9 cycles of treatment at 6-week intervals • Tumor response evaluation: weeks 12, 24, 36, and 48 6 weeks or more frequently, if clinically indicated 8 IT-ta IT tavo-EP EP, intratumoral injection of tavo with electroporation; ta tavo, plasmid interleukin-12.
Phase 2 (OMS-100): Demographics Schedule A B C Overall 51 N 30 17 4 Age Mean (SD) a 66.8 (10.19) 68.4 (13.47) 58.8 (3.30) 66.7 (11.18) Male 16 (53.3%) 13 (76.5%) 4 (100%) 33 (64.7%) Gender Female 14 (46.7%) 4 (23.5%) 0 28 (35.3%) 0 21 (70.0%) 7 (41.2%) 3 (75.0%) 31 (60.8%) ECoG PS 1 9 (30.0%) 10 (58.8%) 1 (25.0%) 20 (39.2%) III b 6 (20.0%) 3 (17.6%) 0 9 (17.6%) Stage III c 13 (43.3%) 5 (29.4%) 2 (50.0%) 20 (39.2%) IV M1a 8 (26.7%) 5 (29.4%) 1 (25.0%) 14 (27.5%) IV M1b 3 (10.0%) 2 (11.8%) 0 5 (9.8%) IV M1c 0 2 (11.8%) 1 (25.0%) 3 (5.9%) Mutant 10 (33.3%) 5 (29.4%) 2 (50.0%) 17 (33.3%) BRAF Status Wild type 13 (43.3%) 9 (52.9%) 1 (25.0%) 23 (45.1%) Unknown 7 (23.4%) 3 (17.7%) 1 (25.0%) 11 (21.5%) 9 BRAF, proto-oncogene B-raf BR
Phase 2 (OMS-100): Treatment History Prior Therapy Cytokine 13 (43.3%) 7 (41.2%) 0 20 (39.2%) CTLA4 9 (26.7%) 7 (41.2%) 2 (50%) 17 (33.3%) PD-1 / PD-L1 4 (13.3%) 7 (41.2%) 2 (50%) 13 (25.5%) 1 (3.3%) 1 (5.9%) 0 2 (3.9%) Cytokine+ CTL 3 (10%) 3 (17.6%) 1 (25%) 7 (13.7%) A4 5 (16.7%) 6 (35.3%) 0 11 (21.6%) BRAF/MEK Other Prior lines 0 10 (33.3%) 4 (23.5%) 2 (50%) 16 (31.4%) 1 10 (33.3%) 3 (17.6%) 0 13 (25.5%) 2+ 10 (33.3%) 10 (58.8%) 2 (50%) 22 (43.1%) BR BRAF, proto-oncogene B-raf; CT CTLA-4, cytotoxic T-lymphocyte – associated antigen 4; MEK, mitogen-activated protein kinase ; PD-1, programmed cell death protein 1; PD PD PD-L1 L1, programmed death-ligand 1. 10
Phase 2 (OMS-100) Demonstrated Clinical Monotherapy Activity in Advanced Melanoma Patients 30% 77% 21% 50% Complete Best Overall Patients with regression Disease Control Response Rate* Response Rate* of >1 non-treated lesion Rate* 100% 100% Untreated Lesions Treated Lesions DS Longest Diameters 50% 50% 0% 0% -50% -50% -100% -100% 11
Phase 2 Category Event All grades (%) Grade 3 (%) (OMS-I100) Any Any 45 (88.2%) 6 (11.8%) Procedural Procedural pain 37 (72.5%) 4 (7.8%) Injection site reactions Injections site discoloration 6 (11.8%) SAFETY: TEAE Regional pain 6 (11.8%) Injection site inflammation 5 (9.8%) Injection site pain 2 (3.9%) 1 (2.0%) Treatment related All seen in > 1 patient Injection site discharge 2 (3.9%) All grade ≥ 3 Ecchymosis 2 (3.9%) Injection site erythema 2 (3.9%) Skin Rash 4 (7.8%) Cellulitis 4 (7.8%) 1 (2.0%) Skin disorder NOS 2 (3.9%) Constitutional Fatigue 7 (13.7%) Pyrexia 2 (3.9%) Chills 2 (3.9%) Psychiatric Anxiety 2 (3.9%) 12
Phase 2 (OMS-100) – Overall response over time (N = 48) DS Longest Diameters – All Lesions (%) NR transient 100 50 0 -50 durable -100 0 6 12 Months 13
Phase 2 (OMS-100) Retrospective analysis of patients who received subsequent PD-1/PD-L1 inhibitors IT-tavo-EP Schedule 1-5-8 (N = 18) Repeat cycle every 90 days Day Day Day D/C Anti – PD-1/PD-L1 + N = 4 1 5 8 IT-tavo-EP Followed for intervening therapy N = 2 N = 6 response N = 3 N = 14 Anti – PD-1/PD-L1 directly Repeat cycle following IT-tavo-EP N = 5 every 6 weeks N = 8 Day Day Day D/C 1 8 15 IT-tavo-EP Pre – and post – IT-tavo-EP PBMC and TIL were interrogated for phenotypic and IT-tavo-EP functional antitumor responses Schedule 1-8-15 14 (N = 16) D/C , discontinued; IT-tavo-EP , intratumoral injection of tavo with electroporation; PBMC , peripheral blood mononuclear cells; PD-1 , programmed cell death protein 1; PD-L1 , programmed death-ligand 1; tavo , plasmid interleukin 12; TIL , tumor-infiltrating lymphocyte.
Phase 2 (OMS-I100): IT-TAVO Followed by Anti-PD-1 Therapy IT-TAVO alone: ORR = 31% Without With Anti-PD-1 alone: ORR = 20-40% Best Overall Intervening Intervening Response Therapy Therapy N=8 N=6 IT-TAVO followed by anti-PD-1 (n=14): ORR = 64% CR 4 (50%) 1 (17%) IT-TAVO followed by anti-PD-1 with NO PR 2 (25%) 2 (33%) intervening therapy (n=8): SD 1 (12.5%) 1 (17%) ORR = 75% PD 1 (12.5%) 2 (33%) Higher Response Rates Than Those from Either Monotherapy 15
Rationale for Combination of TAVO and Anti-PD-1 Blockade PD-1 Blockade Hypothesis: Activation of the PD-1 checkpoint in distant, untreated tumors blunts the effectiveness of TILs generated by tavo 16
Phase 2 (OMS-102) Metastatic Melanoma Combination (tavo + pembro) Trial Design o Patients were selected using CTLA4 hi PD1 hi TIL phenotype o 3 week treatment cycles with pembro administered as a 30-minuted IV infusion at Day 1 of every cycle (flat dose of 200 mg) o Patients treated with IT-TAVO-EP on days 1, 5 and 8 of every 6 weeks IT - TAVO-EP IT - TAVO-EP IT - TAVO-EP P P P P P Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 … P = Pembrolizumab treatment 17
Phase 2 (OMS-102): ORR of combination (tavo + pembro) 102-001 102 001-003 003 102 102-001 001-004 004 102 102-001 001-009 009 102 102-001 001-013 013 102 102-001 001-020 020 102-001 102 001-022 022 102 102-001 001-026 026 102 102-001 001-028 028 102 102-001 001-030 030 102 102-001 001-032 032 * 102 102-007 007-003 003 102 102-001 001-009 009 102-001 102 001-024 024 Complete response 102 102-001 001-029 029 Partial response 102 102-001 001-017 017 Stable response 102 102-001 001-023 023 Post-treatment Pre-treatment Post-treatment Post-treatment Progressive disease 102 102-001 001-016 016 (Week 12) – PD by (Week 48) – PR* (Week 60) – PR* Continuing treatment 102-007 102 007-008 008 RECIST Days on IP-tavo-EP + pembrolizumab 102 102-001 001-019 019 Days on pembrolizumab only 102 102-001 001-002 002 Days off treatment with continued response 102-001 102 001-001 001 Off study – patient decision * 102 102-001 001-007 007 102 102-001 001-011 011 3 6 12 12 15 15 18 18 21 21 24 24 27 27 30 30 33 33 Tim Time (mon (month ths) 18 *PR by clinical assessment
Agenda • Rationale of cytokine choice and Electroporation delivery • Clinical data in metastatic melanoma • Clinical data in metastatic TNBC 19
Metastatic Triple Negative Breast Cancer (TNBC) Patients are ineligible for HER2 and Urgent need for additional ER-targeted therapies therapeutic options in TNBC Disease progression is rapid, and Poor overall survival for chemotherapy responses are not metastatic patients durable Novel targeted therapies (e.g., PARP inhibitors) Unmet need is are only suitable for select patient segments likely to endure Checkpoint inhibition with PD-(L)1 monotherapy is Need for IO only effective in a minority of patients combos 20
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