Slide 1: Interleukin-12 (IL-12) KOL Roundtable
Interleukin-12 (IL-12) KOL Roundtable NASDAQ: PDSB | April 21, 2023
Slide 2: Forward Looking Statements
Forward Looking Statements Certain information in this presentation may include forward-looking statements (including within the meaning of Section 21E of the United States Securities Exchange Act of 1934, as amended, and Section 27A of the United States Securities Act of 1933, as amended) concernin
Slide 3: Disclaimer
Disclaimer PDS Biotech is hosting this roundtable Each panelist is speaking at the request of PDS Biotech Information presented is consistent with FDA guidelines
Slide 4: Introducing our Panel
Introducing our Panel Dr. James Gulley Co-Director of the Center for Immuno-Oncology National Cancer Institute Dr. Jeffrey Schlom Co-Director of the Center for Immuno-Oncology National Cancer Institute
Slide 5: Today's Agenda
Today’s Agenda 5 Welcome and Introductions Dr. Lauren V. Wood History of IL-12 and NHS-IL12/PDS0301 Dr. James Gulley Preclinical and Mechanistic Studies of NHS-IL12/PDS0301 Dr. Jeffrey Schlom Clinical Studies of NHS-IL12/PDS0301 Dr. James Gulley Panel Discussion Moderated by Dr. Lauren V. Wood Closi
Slide 6: History of IL-12 and NHS-IL12 / PDS0301
History of IL-12 and NHS-IL12 / PDS0301 Dr. James Gulley
Slide 7: Investigations elucidate the mechanisms of IL-12 anti-tumor activity
Investigations elucidate the mechanisms of IL-12 anti-tumor activity Modified from Trinchieri G, Nature Reviews Immunology 2003 DC IL-12 Antigen processing & presentation
Slide 8: 1994: Early clinical development of IL-12
1994: Early clinical development of IL-12 Day 1 Test dose 15 Cycle 1 19 35 Cycle 2 40 Tumor measurement 50 Schema of Phase 1: Day 1 Cycle 1 (dosed at MTD) 5 Schema of Phase 2: 500 ng/kg defined as the MTD Explanation: Mouse and monkey data show that the ‘test dose’ in the phase one trial reduced the
Slide 9: IL-12 de-sensitization associated with counter-induction of IL-10
IL-12 de-sensitization in patients is associated with counter-induction of IL-10 The first dose of IL-12 increases production of Th1 cytokines such as IFN-γ and TNF-α Frequent, repeated dosing was associated with declining IFN-γ and TNF-α levels, and a persistent elevation of the Th2 cytokine, IL-10
Slide 10: Recombinant IL-12 has failed due to limited efficacy and toxicity
After well over a decade in the clinic, recombinant IL-12 has failed due to limited efficacy and toxicity Phase 2 Selected Phase I Limited efficacy observed in RCC and melanoma Promising activity against lymphomas Immunomodulatory effects clearly demonstrated Toxicities problematic, tolerability imp
Slide 11: Re-thinking IL-12 immunotherapy
Re-thinking IL-12 immunotherapy A strategy for success with NHS-IL12 (PDS0301): NHS-IL12 targets IL-12 delivery to the tumor, increasing exposure at the tumor site while reducing systemic exposure Further improved tolerability due to the reduced potency of NHS-IL12 NHS-IL12 is a large macromolecule
Slide 12: NHS-IL12 - Molecule Overview
NHS-IL12 - Molecule Overview Molecule Composition M9241 (NHS-IL12) is an immuno-cytokine comprised of two IL-12 heterodimers each fused to one of the H-chains of the IgG NHS76 (fully human) antibody It is a complex molecule with several glycosylation sites IL-12 has been genetically modified to elim
Slide 13: MOA: Innate & Adaptive Immunity Driving Force
MOA: Innate & Adaptive Immunity Driving Force Distinct Mechanisms for IL-12 as a Tumor Targeting Therapy Induces differentiation of naïve CD4+ T-cells to the Th1 phenotype Increases the proliferation and lytic capacity of CD8+ cytotoxic T cells and NK cells Promotes IFN-γ production via NK & T-cells
Slide 14: Effector programing of CD8+ T-cells dependent on APC in TME
Effector programing of CD8+ T-cells dependent on APC in TME CD8+ T cells in tumor-draining lymph nodes maintain a TCF1+ stem-like program Tumor-specific CD8+ T cells migrate to the tumor in the stem-like state CD8+ T cells only acquire the canonical effector program within the tumor Effector program
Slide 15: Kinetic Analysis of Tumor Localization Following s.c. Administration
Kinetic Analysis of Tumor Localization Following s.c. Administration of AF750-labeled NHS-muIL12 and BC1-muIL12 15 chTNT is a mouse/human chimeric Ab 131I-chTNT is a targeted radiotherapeutic Image at right shows biodistribution of 131I-chTNT in a patient with lung cancer. 131I-chTNT is licensed in
Slide 16: Preclinical and Mechanistic Studies of NHS-IL12/PDS0301
Preclinical and Mechanistic Studies of NHS-IL12/PDS0301 Dr. Jeffrey Schlom
Slide 17: Components of Effective Cancer Immunotherapy
Components of Effective Cancer Immunotherapy Source: Schlom and Gulley. JAMA, 2018
Slide 18: Potential of IL-12 as an anti-cancer therapy
Potential of IL-12 as an anti-cancer therapy: Bridges host innate and adaptive immunity Produced by activated APCs (macrophages, DCS, neutrophils, B cells) Drives Th1 differentiation of helper T cells Promotes IFN-γ production via NK & T cells Increases proliferation and lytic capacity of NK, NKT, a
Slide 19: Tumor Localization Kinetics of NHS-muIL12 and BC1-muIL12
Tumor Localization Kinetics of AF750-labeledNHS-muIL12 and BC1-muIL12 (sc) MC38 LLC Antitumor Effect of NHS-muIL12 vs. muIL12 (sc) Fallon…Schlom, Greiner. Oncotarget, 2014; Greiner…Schlom. Immunotargets Ther., 2021
Slide 20: Combination of PDS0101, NHS-IL12 and Bintrafusp alfa Reduced Tumor Volume
The Combination of PDS0101, NHS-IL12 and Bintrafusp alfa Reduced Tumor Volume and Increased T-cell Clonality in TC-1–bearing Mice Source: Smalley Rumfield…Schlom, Jochems. J Immunother Cancer. 2020
Slide 21: PDS0301 Accumulates in Tumors and Promotes T Cell Infiltration
PDS0301 (NHS-IL12) Accumulates in Tumors and Promotes PDS0101 Induced CD8 and CD4 T Cell Infiltration and Expansion in Tumors – Maximum T Cell Accumulation in Tumor with All Three Agents 21 PBS Control PDS0301 (NHS-IL12) PDS0101 vaccine PDS0101 + PDS0301 PDS0101 + PDS0301 + checkpoint inhibitor
Slide 22: Hypothesis: Necrosis-inducing Agents Will Increase NHS-IL12 Targeting
Hypothesis: Necrosis-inducing Agents Will Increase NHS-IL12 Targeting to the Tumor and Increase Immune Activation Day 17 Docetaxel causes necrosis in a dose-specific manner Tumoral NHS-IL12
Slide 23: Anti-tumor Activity of Docetaxel + NHS-IL12
Anti-tumor Activity of Docetaxel + NHS-IL12
Slide 24: Docetaxel and NHS-IL-12 Combination Independent of PD-L1 Expression
Docetaxel and NHS-IL-12 Combination Therapy Independent of PD-L1 Tumor Expression MC38-PD-L1 KO: MC38 cells were co-transfected recombinant Cas9 and a RNA targeting murine PD-L1 PD-L1 negative cells were cloned and used in subsequent studies Model of Primary Checkpoint Resistance Cells made and char
Slide 25: Exploiting Immunotherapy Combinations With HDAC Inhibition
FDA-approved HDACi Indication Vorinostat Cutaneous T cell lymphoma Romidepsin Cutaneous & peripheral T cell lymphoma Belinostat Peripheral T cell lymphoma Tucidinostat Cutaneous T cell lymphoma Panobinostat Multiple myeloma HDACi in solid tumors Exploiting Immunotherapy Combinations With HDAC Inhibi
Slide 26: Exploiting Immunotherapy Combinations with NHS-IL12
Exploiting Immunotherapy Combinations with NHS-IL12 ABSTRACT
Slide 27: Entinostat plus NHS-IL12
Days Post-Tumor Implant Tumor Volume (mm3) EMT6 (BrCa) NHS-IL12 PBS ENT CR: 0/5 1/7 0/7 3/7 7/7 0/7 Days Post-Tumor Implant Tumor Rechallenge Survival Kristin Hicks ENT+NHS-rmIL12 rmIL-12 ENT+rmIL-12 Entinostat plus NHS-IL12 Source: Hicks…Schlom, Gameiro. Nat Commun, 2021 Exploiting Immunotherapy Co
Slide 28: Can NHS-IL12 Plus Entinostat Overcome αPD-1/-L1 Refractory Tumors?
79% TGI: 100% 63% Cures: 40% 100% 20% Can NHS-IL12 Plus Entinostat Overcome αPD-1/-L1 Refractory Tumors Due to Defects in APM/IFNγ Signaling? Source: Minnar...Schlom, Gameiro. J Immunother Cancer, 2022
Slide 29: NHS-IL12 Synergizes with Entinostat to Suppress Refractory Tumors
M2 to M1 shift Activated CD8+ TILs Increased CD8/Tregs TC-1/a9 CMT.64 RVP3 TC-1/a9 TME NHS-IL12 Synergizes with Entinostat to Suppress αPD1/αPDL1 Refractory Tumors
Slide 30: Components of Effective Cancer Immunotherapy
Components of Effective Cancer Immunotherapy Source: Schlom and Gulley. JAMA, 2018
Slide 31: Clinical Studies of NHS-IL12 / PDS0301
Clinical Studies of NHS-IL12 / PDS0301 Dr. James Gulley
Slide 32: NCI Phase 1: First in Human Study
Source: Clinical Cancer Research, 2019 Tumor targeted cytokine (binds DNA in areas of necrosis) Demonstrated safety and biologic activity MTD 16.8 mg/kg s.c. every 28 days NCI Phase 1: First in Human (FIH) Study NCT01417546
Slide 33: NCI Phase 1: FIH Study Design
NCI Phase 1: FIH Study Phase I Study Design (Open Label) Assess the safety, PK and immune impact 3+3 dose-escalation in solid tumors (SAD & MAD portions) Dosing Schedule: Q4W s.c. administration 6 week DLT period Primary Objective MTD Secondary Objectives PK of subcutaneously administered NHS-IL12 I
Slide 34: NCI Phase 1 Study: PK Data
NCI Phase 1 Study: PK Data Average PK from patients in the multidose cohort who received at least two cycles Average PK from both the single and multi-dose patients after the first cycle PK data: Trend for increased exposure with increasing dose with a high degree of inter-subject variability. New P
Slide 35: NCI Phase 1: IFN-γ and IL-10 Response to NHS IL-12
NCI Phase 1: INF-γ and IL-10 Response to NHS IL-12 Dose dependent systemic IFN-g release with trough levels going back to baseline Dose dependent IL-10 release with residual levels at Day 14 Average serum cytokine levels from patients in the multi-dose cohort who received at least two cycles Average
Slide 36: NCI Phase 1 clinical activity
N=13 12 mcg/kg vs. 16.8 mcg/kg s.c. q 2 wk MTD not exceeded 11 evaluable for clinical activity 6/11 evaluable had stable disease as best response (with 5/11 having PD at first restaging) NCI Phase 1 NCT01417546
Slide 37: Patient-level response and immune changes
PT Dose Level (mcg/kg) Age Sex Cancer Type BOR Baseline % Change D14 vs Pre % Change D28 vs Pre IL-12 p70 (pg/ml) Non Classical Monocytes Immature NK DP NK Immature NK CD8 CM CD8 EM CD8 60 12.0 65 F Colon PD 0.3 3.8 -42 +130 -15 -10 -53 -30 67 16.8 44 F Cervical PD 0.5 4.9 -33 -18 -59 -39 -21 -37 69
Slide 38: Immune correlates with response in patients treated with NHS-IL12
ki67* NKT 0.0260 ki67+ NK Mature oat ‘ameong _168mco%9 Diss pe ki67+ NKT 0.0079 % Change vs Pre ‘ameghg _168me0%g Diss pe ki67+ CD8 00317 % Change vs Pre International Immunopharmacology 116 (2023) 109736 Contents lists available at ScienceDirect International Immunopharmacology journal homepage: ww
Slide 39: Versamune Platform
References: Gandhapudi SK, et al. 2019. Antigen priming with enantiospecific cationic lipid nanoparticles induces potent antitumor CTL responses through novel induction of a Type I IFN response. J Immunol. 202 (12): 3524-3536. Smalley Rumfield C et al. 2020. Immunomodulation to enhance the efficacy
Slide 40: Versamune-HPV (PDS0101) Phase 1 Clinical Trial
Versamune®-HPV (PDS0101) Phase 1 Clinical Trial: Confirmation of unique potential to induce rapid and strong CD4 and CD8 T-cell responses against a viral target (HPV16) 14 days post-vaccination Strong virus-specific CD8 T-cell responses were also confirmed by Granzyme-b ELISPOT (data not shown) Safe
Slide 41: Bintrafusp Alfa
Bintrafusp Alfa Source: Phase I: Strauss…Gulley. Clin Cancer Res. 2018
Slide 42: Triple combination resulted in tumor control in HPV+ TC-1 model
The combination of PDS0101, bintrafusp alfa and NHS-IL12 (PDS0301) resulted in tumor control in the HPV+ TC-1 syngeneic tumor model Source: Claire Smalley Rumfield et al. J Immunother Cancer 2020;8:e000612
Slide 43: NCI Triple Combination Study Design
NCI Triple Combination Study Design Patients with advanced HPV-related cancers received the combination of bintrafusp alfa at 1200 mg flat dose i.v. q 2wks, M9241(NHS-IL12/PDS0301) at 16.8 mcg/kg s.c. q 4 wks or 8 mcg/kg s.c. q 4 weeks and PDS0101 given as two separate 0.5 ml s.c. injections q 4 wks
Slide 44: Best Overall Response Active Against Diverse HPV16 Cancers
Best Overall Response Active Against Diverse HPV16 Cancers Effective Translation from Preclinical to Human: PDS0101 + PDS0301 + Checkpoint Inhibitor Shows Clinical Activity 44 *HNSCC – head and neck squamous cell carcinomas Higher PDS0301 Dose Cervical Vaginal/Vulvar Anal HNSCC* Reference: Strauss J
Slide 45: Triple Combination Shows Clinical Activity
Effective Translation from Preclinical to Human: PDS0101 + PDS0301 + Checkpoint Inhibitor Shows Clinical Activity 45 *HNSCC – head and neck squamous cell carcinomas Reference: Strauss J. et al. Phase II evaluation of the triple combination of PDS0101, M9241, and Bintrafusp alfa in patients with HPV
Slide 46: NCI Publications Involving NHS-IL12
NCI Publications Involving NHS-IL12 Tumor-targeted interleukin-12 synergizes with entinostat to overcome PD-1/PD-L1 blockade-resistant tumors harboring MHC-I and APM deficiencies. J ImmunoTher Cancer. 2022 Cure of syngeneic carcinomas with targeted IL-12 through obligate reprogramming of lymphoid an
Slide 47: Panel Discussion
Panel Discussion
Slide 48: Closing Remarks
Closing Remarks Dr. Lauren V. Wood