Marker Therapeutics, Inc. · NASDAQ:MRKR
Marker Therapeutics — Technical Presentation (2019)
66 slides from Marker Therapeutics's technical presentation, 2019
Slide 1: Administering AML-directed DLIs to patients with AML or MDS Post-Allogeneic HSCT Relapse
Administering AML-directed DLIs to patients with AML or MDS Post- Allogeneic HSCT Relapse Premal Lulla, Swati Naik, Ifigeneia Tzannou, Shivani Mukhi, Manik Kuvalekar, Catherine Robertson, Carlos A Ramos, George Carrum, Rammurti Kamble, Jasleen Randhawa, Adrian P Gee, Bambi Grilley Malcolm K Brenner,
Slide 2: Acute Myeloid Leukemia
Acute Myeloid Leukemia 16% Cured 20% AML Adverse risk/relapsed Adverse risks ~26,000/yr >CR2 Complex cytogenetics Monosomy 7 80% MDS→ AML t-AML Allo-HSCT MLL-r potentially curative FLT3/DNMT3A etc Koreth J et al, DeAngelo DJ JAMA 2009
Slide 3: Outcomes of AML patients post-alloHSCT
Outcomes of AML patients post-alloHSCT 18 month Relapse rate post-HSCT MAC-SCT RIC-SCT 14% 48% 1-year survival after relapse: 23% BMT-CTN 0901. Scott et al J Clin Oncol. 2017 Bejanyan et al BBMT 2015
Slide 4: Donor lymphocytes and adoptive T cell transfer
Donor lymphocytes SCT recipient SCT donor Blood draw Antigen specificity Adoptive T cell transfer Infusion Cell expansion Tumor-specific T cells
Slide 5: MultiTAA-T cells for AML/MDS
MultiTAA-T cells for AML/MDS TAA Freq. WT1 72-90% PRAME 40-60% Survivin 90-100% NY-ESO1 0-36%
Slide 6: Our approach
Our approach • Simultaneously target multiple TAAs • Target multiple epitopes (CD4 and CD8) within each antigen • T cells with native T cell receptor specificity (non-engineered)
Slide 7: MultiTAA Manufacture
MultiTAA Manufacture Overlapping pepmixes DC PBMCs MultiTAA T cells
Slide 8: Profile of MultiTAA-T cells
Profile of MultiTAA-T cells Phenotype Alloreactive 100% 30% potential 80% 25% % Positive cells % Specific lysis 60% 20% 15% 40% 10% 20% 5% 0% CD3+ CD4+ CD8+ RO+/ RO+/ RO+/ 62L+/ 62L+/ 62L-/ 0% CCR7- CCR7+ CCR7- n=24
Slide 9: MultiTAA T cell specificity
MultiTAA T cell specificity PRAME NYESO1 Survivin WT1 1000 100 SFC/2x105 10 1 0.1
Slide 10: MultiTAA T cell specificity
MultiTAA T cell specificity PRAME NYESO1 Survivin WT1 Line clones 1000 100000 100 10000 SFC/2x105 1000 # of clones 10 100 mean = 5382 clones (1697 – 16227) 1 10 n=12 0.1 1
Slide 11: Phase I trial - ADSPAM
Phase I trial - ADSPAM Any patient with AML/MDS post allo-HSCT Donor-derived multiTAA T cells GROUP A - Adjuvant Dose Escalation AML/MDS patients 30 days post allo-HSCT DL1 5x106 cells/m2 DL2 1x107 cells/m2 GROUP B – Active disease DL3 2x107 cells/m2 AML/MDS patients 30 days post allo-HSCT
Slide 12: Clinical trial: Current status
Clinical trial: Current status Patients Enrolled: 27 patients (24 AML and 3 MDS) Patients Treated: 20 patients (0.5-2x107 cells/m2) Grade II or lesser Grade III 3 (all grade I elevation in 1 grade III LFT elevation (resolved with LFTs 0.5 mg/kg prednisone)
Slide 13: Patients infused – ARM A
Patients infused – ARM A Age/ ID Disease Prior Treatments G 1* 57/F FLT3-ITD CIA → Sorafenib → CIAx2 → RIC-SCT 2 18/F FLT3-ITD Bortezomib/Dauno EC → sorafenib → MAC-SCT 5 55/F MLL-r 7+3 → HiDAC → MAC-SCT 6 70/F AML CR3 7+3 → HiDAC → CIA → RIC-SCT-Relapse → 7+3 7 53/F DNMT3a 7+3 → HiDAC → MAC-SCT 10
Slide 14: Outcomes – ARM A
Outcomes – ARM A Wk 4 Marrow ID Disease Relapse? Status at last f/up (% blasts) No, but bone Treated on ARM B (9 mo’s post- 1* FLT3-ITD 0 relapse infusion) 2 FLT3-ITD 0 No Alive in CR (2.5 years) No, CNS relapse, 5 MLL-r 0 Alive in CR (2 years) Local Rx alone No, CNS relapse 6 AML CR3 0 Alive in CR
Slide 15: Patients infused – ARM B
Patients infused – ARM B GROUP B: Active AML: 7 patients treated for active AML Ag ID Disease Prior Treatments e/G 3 70/M IDH1mut 7+3 → decitabine → IDH inhib → cutis relapse → CIA → RIC-SCT→ Relapse 4 16/M MDS→ AML Double cord SCT → AML Relapse → C → haplo-SCTx2 → Relapse 1* 57/F FLT3-ITD CIA → Sor
Slide 16: Outcomes – ARM B
Outcomes – ARM B ID Disease Day 0 Week 4 Response Status at last f/up Stable skin 3 IDH1mut Skin relapse NR PD (3 months) → HiDAC chemo lesion 4 MDS→ AML 30% blasts 30% NR PD (4 weeks) → Hospice (4 mo) 1* FLT3-ITD 4 bone lesions All resolved CR Relapse (13 mo) → 7+3 chemo 8 Induc. failure 50% blasts
Slide 17: Outcomes – ARM B
Outcomes – ARM B ID Disease Day 0 Week 4 Response Status at last f/up Stable skin 3 IDH1mut Skin relapse NR PD (3 mo) → HiDAC chemo lesion 4 MDS→ AML 30% blasts 30% NR PD (4 wks) → Hospice 1* FLT3-ITD 4 bone lesions All resolved CR CR (13 mo) →Relapse → 7+3 chemo 8 Induc. failure 50% blasts 15% PR P
Slide 18: Tracking infused clones in vivo
Tracking infused clones in vivo Rationale: • Infused lymphocytes are not gene modified • Leukemia specific T cell clones enriched in infused line Approach: • TCR Deep sequencing of donor-T cell product • Track expansion of line-derived clones in vivo
Slide 19: In vivo expansion of line clones
In vivo expansion of line clones Overall Fold change (from baseline) Marrow 2 60% Productive Frequency 382 line-exclusive 0.5% line-exclusive clones clones 1.5 40% 1 20% n=12 n=4 0.5 0% By week 4 Week 4
Slide 20: Responders vs Non-responders
Responders vs Non-responders IFNγ ELISPOT By disease response Responders n=9 Relapse/progress n=3 120 60% No relapse/progression n=4 Non-responders n=7 %Repertoire SFC/5x105 80 40% 40 20% 0 0% Pre Wk4 Preinfusion By week 4
Slide 21: Clinical course – Pt#1
Clinical course – Pt#1 FLT3mut AML received T cells as adjuvant (120 days post HSCT) 6.1% 7% 1.8% Relapse 16 Prednisone SFC/5x105 14 Prame 12 NYESO1 10 Survivin 8 WT1 6 4 2 0 Lesions-4 pre inf 1 Week 8 Mo5
Slide 22: Clinical course – Pt#1
Clinical course – Pt#1 Tumor – antigen expression H+E WT1
Slide 23: Clinical course – Pt#1
Clinical course – Pt#1 Post-decitabine (Mo.10) Post-T cell (Mo.11) 1.45% 2.47% 3.07% 20 240 • CASSSGQAYEQYF 240 • CASSQVFPNTGELFF 15 160 WT1 160 Survivin 10 NYESO-1 80 PRAME 80 5 0 0 0 Post decitabine CR Marrow
Slide 24: Clinical course – Pt#8
Clinical course – Pt#8 TAA expression % cells Intensity PRAME 50-75% 2+ Survivin <10% 2+ 45% 1000 NYESO1 <10% 1+ WT1 <10% 1+ 800 60 45% 30% 600 ANC SFC/5x105 Blasts% WT1 40 Survivin 30% NYESO-1 PRAME 400 15% 20 15% 200 0 0% 0% 0 Pre-inf Mo.1 Pre-inf Mo.1 Mo.4
Slide 25: Summary
Summary course - SM • Leukemia-directed donor T cell infusions are safe • Mediate anti-tumor effects • In vivo expansion superior in responders • Antigen spreading studies ongoing • Investigation of immune escape mechanisms
Slide 26: Administering AML-directed DLIs to patients with AML or MDS Post-Allogeneic HSCT Relapse
Administering AML-directed DLIs to patients with AML or MDS Post- Allogeneic HSCT Relapse Premal Lulla, Swati Naik, Ifigeneia Tzannou, Shivani Mukhi, Manik Kuvalekar, Catherine Robertson, Carlos A Ramos, George Carrum, Rammurti Kamble, Jasleen Randhawa, Adrian P Gee, Bambi Grilley Malcolm K Brenner,
Slide 27: Targeting Lymphomas Using Non-Engineered, Multi-Antigen Specific T Cells
Targeting Lymphomas Using Non- Engineered, Multi-Antigen Specific T Cells George Carrum, Premal Lulla, Ifigeneia Tzannou, Ayumi Watanabe, Manik Kuvalekar, Munu Bilgi, Tao Wang, Rammurti Kamble, Carlos A. Ramos, Rayne Rouce, Bambi J. Grilley, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona
Slide 28: Adoptive T cell transfer overview
PBMCs Blood draw Antigen Specificity Adoptive T cell Patient transfer Infusion Tumor-specific T cells
Slide 29: Our approach
Our approach • Simultaneously target multiple TAAs • Target multiple epitopes (CD4 and CD8) within each antigen • T cells with native T cell receptor specificity (non-engineered)
Slide 30: MultiTAA T cell therapy for lymphoma
MultiTAA T cell therapy for lymphoma MAGEA4 PRAME Survivin NYESO1 SSX2 MultiTAA T cells
Slide 31: MultiTAA-T Cell manufacture
MultiTAA-T Cell manufacture Overlapping pepmixes DC Activation Expansion PBMCs MultiTAA T cells
Slide 32: MultiTAA-T Cell Phenotype
MultiTAA-T Cell Phenotype 100 80 % Positive cells 60 40 20 n=39 0 CD3 CD4 CD8 NK DC TCM TEM
Slide 33: MultiTAA-T Cell Specificity
MultiTAA-T Cell Specificity 1000 SFC/2x105 cells 100 10 1 0.1 0 PRAME 1 SSX2 2 MAGEA4 3 NYESO1 4 Survivin 5 6
Slide 34: Multi TAA-T Cell Autoreactivity
Multi TAA-T Cell Autoreactivity 20% % Specific Lysis 10% 0% 0 0.5 E:T of1 20:1 1.5 2
Slide 35: Clinical Trial: Eligibility
Clinical Trial: Eligibility Any patient >18 yrs with HL or NHL Active disease - in 2nd or subsequent relapse - in 1st relapse for indolent lymphoma after 1st line therapy for relapse - in 1st relapse if immunosuppressive chemotherapy contraindicated - primary refractory disease or persistent disease
Slide 36: Safety of MultiTAA T cells - Antigen escalation
Safety of MultiTAA T cells - Antigen escalation Antigen Escalation Phase = fixed dose 5x106/m2 – 2 pts/stage: Day 0: PRAME-specific T cells Day 28: PRAME and SSX-specific T cells Stage Two: Day 0: PRAME and SSX-specific T cells Day 28: PRAME/SSX/MAGE-specific T cells Stage Three: Day 0: PRAME/SSX/MA
Slide 37: Safety of MultiTAA T cells - Dose escalation
Safety of MultiTAA T cells - Dose escalation PRAME/SSX/MAGE/NYESO1/Survivin-specific T cells: 2-4 pts at each level, 2 infusions 14 days apart Dose Level 1: Day 0 and 14: 5x106 cells/m2 Dose Level 2: Day 0 and 14: 1x107 cells/m2 Dose Level 3: Day 0 and 14: 2x107 cells/m2
Slide 38: Clinical Trial: Treatment
Clinical Trial: Treatment • 33 patients infused
Slide 39: Clinical Trial: Treatment
Clinical Trial: Treatment • 33 patients infused Antigen escalation (n=4) Group A: Dose escalation In remission (n=14) Group B: Dose escalation Active lymphoma (failed prior lines) (n=11) Antigen escalation (n=4)
Slide 40: Clinical Trial: Treatment
Clinical Trial: Treatment -33 patients infused (0.5-2x107 cells/m2) - 12 HL - 19 aggressive NHL (DLBCL/mantle/peripheral T) - 2 with composite lymphoma - No lymphodepletion - No adverse events
Slide 41: Pt1 (HL) – Clinical and Immune effects
Pt1 (HL) – Clinical and Immune effects A Pre T cells B Targeted Antigens Targeted antigens 50 90 40 80 30 SSX2 70 PRAME 20 60 10 SFC/5x10e55 SFC/2x10 0 50 Pre Post Post CTLs + radiation Post T cells 40 Non-targeted antigens 140 Non-targeted antigens 30 120 AFP 100 NYESO1 20 80 60 10 40 200 0 Prame S
Slide 42: Pt2 (NHL) - Clinical and Immune effects
Pt2 (NHL) - Clinical and Immune effects Mth 39 Pre-Infusion Targeted antigens Non-targeted antigen 200 45 Survivin NYESO1 180 40 MAGEA4 MAGEC1 SSX2 160 35 PRAME SFC/2x105 140 30 120 25 100 20 80 15 60 10 40 5 20 0 Pre PRE MTH3 Mth3 Mth9 MTH9
Slide 43: Clinical Outcomes – Adjuvant
Clinical Outcomes ––Adjuvant ClinicalOutcomes Adjuvant - 18 patients infused as adjuvant -15/18 in remission (median 19 months)
Slide 44: Clinical Outcomes – Adjuvant
Clinical Outcomes – Adjuvant ID Age/Sex Disease Prior Therapies Response to T cell therapy (duration) 1* 39/M HL & DLBCL ABVD → RICE → ASCT CCR (>3 years) 2* 78/F DLBCL R→RCHOP In remission (8 mo) →relapse 3* 78/F DLBCL R→RCHOP → multiTAA T cells → R-Bendamustine CCR (>3 years) 4* 21/M HL ABVD → Bre
Slide 45: Clinical Outcomes – Active disease
Clinical Outcomes – Active disease - 15 patients treated for active disease - 6 CRs; 4 SD; 5 PD
Slide 46: Clinical Outcomes – Active disease
Clinical Outcomes – Active disease ID Age/Sex Disease Prior Therapies Response to multiTAA T cells (duration) ABVD → ICE → Cis-Gem→ XRT →ASCT→ Stable disease (5 mo) → Off study [Revilimid (5 mo) →PD1] 1* 31/F HL EBV T cells→Brentuximab→Yttrium90 → CART-CD30 2* 55/F HL/NHL RCHOP + XRT → ICE → ASCT CR
Slide 47: Summary to date
Summary to date • Safe to date • Feasible adjuvant and treatment • In vivo expansion of T cells directed to targeted antigens • Antigen/Epitope spreading • Clinical benefit
Slide 48: Targeting Lymphomas Using Non-Engineered, Multi-Antigen Specific T Cells
Targeting Lymphomas Using Non- Engineered, Multi-Antigen Specific T Cells George Carrum, Premal Lulla, Ifigeneia Tzannou, Ayumi Watanabe, Manik Kuvalekar, Munu Bilgi, Tao Wang, Rammurti Kamble, Carlos A. Ramos, Rayne Rouce, Bambi J. Grilley, Adrian P. Gee, Malcolm K. Brenner, Helen E. Heslop, Cliona
Slide 49: Adoptive T cell therapy for ALL targeting multiple tumor associated antigens
Adoptive T cell therapy for ALL targeting multiple tumor associated antigens Swati Naik, Premal Lulla, Ifigeneia Tzannou, Shivani Mukhi, Manik Kuvalekar, Catherine Robertson, George Carrum, Rammurti Kamble, Adrian P Gee, Bambi Grilley, Robert Krance, Malcolm K Brenner, Helen E Heslop, Juan F Vera, S
Slide 50: ALL Relapse after HSCT
ALL Relapse after HSCT • Leukemic relapse is major cause of treatment failure after HSCT – Incidence of relapse: 24-35% • Poor prognosis for pts who relapse – Particularly those who relapse early post-HSCT – Overall survival: 7- 32% Fagioli Hematologica 2013 Porter et al , BBMT 2011 Arellano, BBMT 2
Slide 51: Prevention of ALL relapse
Prevention of ALL relapse • Strategies to prevent relapse –Prophylactic use of targeted agents (e.g. TKIs) –Modulation of immune suppression • Promote immune reconstitution resulting in GvL effect –Immunotherapeutic intervention with DLIs • Enhance GvL effect Wayne, Hematology 2017 De Lima,BBMT 2013
Slide 52: Donor lymphocyte infusion limitations
SCT recipient SCT donor Blood draw Donor lymphocytes Adoptive T cell transfer • Low tumor-specific T cell Infusion frequency • High frequency of alloreactive cells (GvHD)
Slide 53: Tumor-specific T cell generation
Donor lymphocytes SCT recipient SCT donor Blood draw Antigen specificity Adoptive T cell transfer Infusion Cell expansion Tumor-specific T cells
Slide 54: MultiTAA T cell therapy for AML
MultiTAA T cell therapy for AML TAA Freq. WT1 70% PRAME 65% Survivin 40%
Slide 55: MultiTAA-T Cell manufacture
MultiTAA-T Cell manufacture Pepmix spanning full length WT1, PRAME, Survivin DC Activation Expansion PBMCs MultiTAA T cells
Slide 56: MultiTAA T cell profile
MultiTAA T cell profile 120% Phenotype 40% Safety % Positive cells % Specific lysis 30% 80% 20% 10% 40% 0% n=11 0% -10% CD3 CD4 CD8 CD3+/ CD3+/ 20:1 RO+/ RO+/ 62L+ 62L-
Slide 57: MultiTAA T cell profile
MultiTAA T cell profile 1000 SFC/2x105 Specificity 100 10 1 0 1 2 3 4 Prame Survivin WT1
Slide 58: Study design (STELLA)
Study design (STELLA) Any patient with ALL who received an allogeneic SCT from a family donor DL1 5x106 cells/m2 DL2 1x107 cells/m2 DL3 2x107 cells/m2 Given after day +30 post-transplant
Slide 59: Patients infused – STELLA
Patients infused – STELLA ID Age/G Disease Prior Treatments Dose level 1 5/F Ph+ ALL Induction chemo → Primary induction failure → MRD SCT 1 2 18/F HR- ALL Completed therapy for HR- ALL → Relapse → MRD SCT 1 Completed therapy for HR- ALL → Relapse → MRDSCT→ 3 18/F Ph+ ALL 1 Relapse → Chemo→ CD34+ to
Slide 60: Safety
Safety • No Dose Limiting Toxicities (DLTs) • No GVHD • No CRS/neurotoxicity or other adverse events • Three patients not evaluable per protocol: – received >0.5mg/kg steroids within 4 weeks of infusion – Pt 1 and 12: Stress dose steroids for sepsis – Pt 6: Steroids for elevation of AST/ALT, GVHD ru
Slide 61: Clinical outcomes
Clinical outcomes ID Age/G Disease Dose level Clinical course 2 18/F HR- ALL 1 CR with mixed chimerism for 6 months→ Relapse 3 18/F Ph+ ALL 1 Alive in CR (22 months post-infusion) 4 41/M HR- ALL 1 Alive in CR (28 months post-infusion) 5 8/M Ph+ ALL 1 Died in CR (9 months post-infusion) 9 12/F T-cell
Slide 62: Immune Reconstitution
Immune Reconstitution 350 Pt 3 - CR 35 Pt 4 - CR 20 Pt 2 - Relapse 18 300 30 16 SFC/5x105 SFC/5x105 SFC/5x105 250 25 14 200 20 12 WT1 WT1 WT1 Survivin Survivin 10 Survivin 150 Prame 15 Prame 8 Prame 100 10 6 4 50 5 2 0 0 0 Preinf Wk 4 Preinf Wk 4 Preinf Wk 4
Slide 63: Tumor antigen expression and T cell expansion
Tumor antigen expression and T cell expansion Immune Reconstitution 350 Pt 3 WT1 PRAME 300 250 SFC/5x105 200 WT1 Survivin Pre 150 Prame 100 50 0 neg 4+ Preinf Wk 4
Slide 64: Antigen Spreading
Antigen Spreading Pt 3 Target Antigens Antigen spreading 350 500 AFP WT1 300 MART1 SFC/5x105 Survivin 400 250 MC1 Prame 300 MA3 200 MA2B 150 200 MA1 100 100 NYESO1 50 mageA4 0 0 SSX2 Preinf Wk 4 Preinf Wk 4
Slide 65: Summary
Summary • Feasible for both B-cell and T-cell ALL • Safe to date, well-tolerated • In vivo expansion of tumor-antigen associated T-cells directed to target antigens • Evidence of antigen spreading which may contribute to relapse prevention • May present a safe and effective strategy to prevent leuke
Slide 66: Safety and efficacy of multi-TAA-T cells for Myeloma
Safety and efficacy of multi-TAA-T cells for Myeloma Premal Lulla, Ifigeneia Tzannou, George Carrum, Carlos A. Ramos, Rammurti Kamble, Mrinalini Bilgi, Adrian P. Gee Shivani Mukhi, Betty Chung, Ayumi Watanabe, Manik Kuvalekar, Bambi Grilley, Malcolm K. Brenner, Helen E. Heslop, Juan F. Vera and Ann