Pds Biotechnology Corporation · NASDAQ:PDSB
Pds Biotechnology — Technical Presentation (April 2023)
48 slides from Pds Biotechnology's technical presentation, Apr 21, 2023
Slide 1: Interleukin-12 (IL-12) KOL Roundtable
Interleukin-12 (IL-12) KOL Roundtable Precision Designed Science For Immunotherapy 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 3
Slide 4: Introducing our Panel
Introducing our Panel Dr. James Gulley Dr. Jeffrey Schlom Co-Director of the Center for Co-Director of the Center for Immuno-Oncology Immuno-Oncology National Cancer Institute National Cancer Institute 4
Slide 5: Today's Agenda
Today’s Agenda 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 Closing
Slide 6: History of IL-12 and NHS-IL12 / PDS0301
History of IL-12 and NHS-IL12 / PDS0301 Dr. James Gulley
Slide 7: Subsequent investigations elucidate the mechanisms of IL-12 anti-tumor activity
Subsequent investigations elucidate the mechanisms of IL-12 anti- tumor activity Antigen processing & presentation IL-12 DC Modified from Trinchieri G, Nature Reviews Immunology 2003 7
Slide 8: 1994: Early clinical development of IL-12
1994: Early clinical development of IL-12 Test dose Cycle 1 Cycle 2 Tumor Schema of Phase 1: measurement 500 ng/kg defined as the MTD 1 15 19 35 40 50 Day Cycle 1 (dosed at MTD) Severe toxicity in all patients; two Schema of Phase 2: patient deaths; trial stopped – 1 5 Day Explanation: Mouse and mon
Slide 9: IL-12 de-sensitization in patients is 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,
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 Selected Phase I Phase 2 • Limited efficacy observed in RCC and melanoma • Promising activity against lymphomas • Immunomodulatory effects clearly demonstrated • Toxicities problematic, tolerabi
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 macrom
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
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 &
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
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 131I-chTNT targeting to lung tumor • 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
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 17 Source: Schlom and Gulley. JAMA, 2018
Slide 18: Exploiting Immunotherapy Combinations With NHS-IL12/PDS0301
Exploiting Immunotherapy Combinations With NHS-IL12/PDS0301 Potential of IL-12 as an anti-cancer therapy: § Bridges host innate and adaptive immunity § Produced by activated APCs (macrophages, DCS, neutrophils, B cells) v Drives Th1 differentiation of helper T cells v Promotes IFN-γ production via N
Slide 19: Tumor Localization Kinetics of AF750-labeled NHS-muIL12 and BC1-muIL12
Tumor Localization Kinetics of AF750-labeled NHS-muIL12 and BC1-muIL12 (sc) Antitumor Effect of NHS-muIL12 vs. muIL12 (sc) MC38 LLC 19 Fallon…Schlom, Greiner. Oncotarget, 2014; Greiner…Schlom. Immunotargets Ther., 2021
Slide 20: 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 20
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 PBS Control PDS0301 (NHS-IL12) PDS0101 + PDS0301 + checkpoint inhibitor PDS0101 vaccine PDS0101 + PDS0301 21
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 C57 Docetaxel causes necrosis in a dose-specific manner Tumoral NHS-IL12 Day 17 No Treatment Docetaxel 22
Slide 23: Anti-tumor Activity of Docetaxel + NHS-IL12
MC38 Docetaxel Tumor Volume (mm r-IL-12 Tumor Volume (mm3) s.c. 1500 el 12 NHS-IL-12 1500 d10 d12 d14 ax L o et S-I mb 1000 rIL-12 Anti-tumor Activity of Docetaxel + NHS-IL12 d0 d7 d9 d11 1000 Docetaxel + c Do NH Co d26 NHS-IL-12 C57Bl/6 Docetaxel Harvest 500 500 Docetaxel + rIL-12 0 0 0 5 10 15 20
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
Slide 25: Exploiting Immunotherapy Combinations With HDAC Inhibition
Exploiting Immunotherapy Combinations With HDAC Inhibition FDA-approved HDACi Indication Vorinostat Cutaneous T cell lymphoma Cutaneous & peripheral T cell Romidepsin lymphoma Belinostat Peripheral T cell lymphoma Tucidinostat Cutaneous T cell lymphoma Panobinostat Multiple myeloma HDACi in solid tu
Slide 26: Exploiting Immunotherapy Combinations with NHS-IL12
Exploiting Immunotherapy Combinations with NHS-IL12 ABSTRACT 26
Slide 27: Entinostat plus NHS-IL12
Exploiting Immunotherapy Combinations with NHS-IL12 Entinostat plus NHS-IL12 Kristin Hicks EMT6 (BrCa) Survival Tumor PBS ENT rmIL-12 ENT+rmIL-12 NHS-IL12 ENT+NHS-rmIL12 Rechallenge 1000 mOS(d) Tumor Volume (mm3) 100 29 PBS ENT 36 NHS-rmIL12 29 TS/A EMT6 Tumor volume (mm 3) ENT+NHS-rmIL12 n/a 800 %
Slide 28: Can NHS-IL12 Plus Entinostat Overcome αPD-1/-L1 Refractory Tumors?
Can NHS-IL12 Plus Entinostat Overcome αPD-1/-L1 Refractory Tumors Due to Defects in APM/IFNγ Signaling? TC-1/a9 CMT.64 RVP3 2 Tumor volume (mm3 x 1000) 2 2 Tumor volume (mm3 x 1000) Tumor volume (mm3 X1000) PBS PBS PBS αPD-L1 αPD-L1 ** αPD-L1 1 1 1 0 0 0 0 5 10 15 20 25 0 10 20 30 40 0 5 10 15 20 25
Slide 29: NHS-IL12 Synergizes with Entinostat to Suppress Refractory Tumors
NHS-IL12 Synergizes with Entinostat to Suppress αPD1/αPDL1 Refractory Tumors TC-1/a9 CMT.64 2000 RVP3 Tumor edge Tumor core 2000 PBS PBS ENT ENT CD8 counts per region Tumor Volume (mm3) Tumor Volume (mm3) NHS-IL12 NHS-IL12 200 ENT + NHS-IL12 ENT+NHS-IL12 ** ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱ 150 PBS ✱✱ *** **** # C
Slide 30: Components of Effective Cancer Immunotherapy
Components of Effective Cancer Immunotherapy 30 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 (FIH) Study
NCI Phase 1: First in Human (FIH) Study • Tumor targeted cytokine (binds DNA in areas of necrosis) • Demonstrated safety and biologic activity • MTD 16.8 µg/kg s.c. every 28 days NCT01417546 Source: Clinical Cancer Research, 2019 32
Slide 33: NCI Phase 1: FIH Study
NCI Phase 1: FIH Study Dose Level* # of pts Tumor Types # of pts Treatment duration Tumor Types (mcg/kg) (MD), # of cycles • Phase I Study Design (Open Label) 0.1 3 Kaposi, Breast, Transitional – Assess the safety, PK and immune impact 0.5 3 CRC (n=2), Mesothelioma – 3+3 dose-escalation in solid tum
Slide 34: NCI Phase 1 Study: PK Data
NCI Phase 1 Study: PK Data Average PK from both the single and Average PK from patients in the C y c le 1 A ll D a y s 80 multi-dose patients after the first multidose cohort who received at least M u ltid o s e P a tie n t s 100 cycle two cycles 80 N H S - IL 1 2 (n g /m l) 60 N H S - IL 1 2 (n g /
Slide 35: NCI Phase 1: INF-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 both the single Average serum cytokine levels from patients in the mul
Slide 36: NCI Phase 1
NCI Phase 1 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) NCT01417546 36
Slide 37: NCI Phase 1: Immune Status at Baseline and Early Changes
NCI Phase 1: Immune Status at Baseline and Early Changes in the Immune Profile After NHS-IL 12 Associated With Best Overall Response (BOR) Baseline % Change D14 vs Pre % Change D28 vs Pre Dose Level PT Age Sex Cancer Type BOR IL-12 p70 Non Classical (mcg/kg) Immature NK DP NK Immature NK CD8 CM CD8
Slide 38: % Change vs Pre
% Change vs Pre 8 ° Intemational Immunopharmacology 116 (2023) 109736 ELSEVIER Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Immune correlates with response in patients with metastatic solid tumors 8 treated with a tumor t
Slide 39: Versamune Platform
Versamune® Platform Versamune® generates right type, potency and quantity of killer T cells 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. 20
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 HPV-specific HPV-specific T-cell Response T-cell Response IFN-γ ELISPOT IFN-γ ELISPOT Pre-treatment Post-t
Slide 41: Bintrafusp Alfa
Bintrafusp Alfa Source: Phase I: Strauss…Gulley. Clin Cancer Res. 2018 41
Slide 42: Combination of PDS0101, bintrafusp alfa and NHS-IL12 Tumor Control
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 42
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
Slide 44: Effective Translation from Preclinical to Human
Effective Translation from Preclinical to Human: PDS0101 + PDS0301 + Checkpoint Inhibitor Shows Clinical Activity Phase 2 Trial Correlates with Preclinical Results Demonstrating Improved Shrinkage of HPV16+ Tumors with the Triple Combination in Multiple Types of HPV-Associated Cancers Checkpoint inh
Slide 45: Effective Translation from Preclinical to Human
Effective Translation from Preclinical to Human: PDS0101 + PDS0301 + Checkpoint Inhibitor Shows Clinical Activity Phase 2 Trial Correlates with Preclinical Results Demonstrating Improved Shrinkage of HPV16+ Tumors with the Triple Combination in ICI Naïve and Refractory Patients Checkpoint inhibitor
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 lymphoi
Slide 47: Panel Discussion
Panel Discussion
Slide 48: Closing Remarks
Closing Remarks Dr. Lauren V. Wood
PDS Biotechnology — Technical Presentation (April 2023) on 6ix