Targeting Immune Checkpoint Proteins and Cells for the Treatment of Cancer Jason Chesney, Deputy Director
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1 The Geoffrey P. Herzig Memorial Symposium for Hematological Malignancies & Bone Marrow Transplantation Targeting Immune Checkpoint Proteins and Cells for the Treatment of Cancer Jason Chesney, Deputy Director
2 Disclosure of Relevant Financial Relationships (none impact my ability to present an unbiased talk) Funding to the UofL for clinical trial testing of ipilimumab (BMS), nivolumab (BMS), pembrolizumab (Merck), TVEC (Amgen) and PFK-158 (ACT) in cancer patients Co-inventor of seven issued U.S. Patents on PFKFB3, PFK-158 and MIF inhibitors for the treatment of cancer (intellectual property owned by the UofL and Picower Institute) Regular service on scientific and clinical advisory boards for Novartis, BMS and Amgen No participation in pharmaceutical company s speakers bureaus
3 How T Cells Kill Cancer Cells Cytotoxic T cell 1 TCR Class I MHC molecule Perforin Granzymes CD8 2 Pore 3 Released cytotoxic T cell Apoptotic target cell Cancer cell Target cell Peptide antigen Cytotoxic T cell
4 T Cells Have 2 Brakes Called Immune Checkpoints: PD1, CTLA4 These brakes serve to block the activation of T cells The feet that push these brakes are PD-L1 and B7.1/2 Feet: PD-L1 & B7.1/2 Brakes: PD1 & CTLA4
5 Antibodies That Block the Two Brakes Include: actla4 (Ipilimumab) and apd1 (Nivolumab/Pembrolizumb) By blocking the brakes, T cells go into overdrive (Pembrolizumab)
6 Phase I Trial of an Anti-PD1 In Patients With Refractory and Terminal Melanoma
7 Should we Block BOTH Brakes at the Same Time?
8 Should we Block BOTH Brakes at the Same Time?
9 Golladay Swartz Baum UofL: #2 Accruing Site
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14 WARNING: Autoimmunities From Immune Checkpoint Inhibitors Can Be Fatal (1-2%) Majority of autoimmune side effects resolve with steroids
15 Immune Checkpoint Inhibitors Should Have Efficacy Against Multiple Cancer Types
16 Phase 1 Trial of Nivolumab With Ipilimumab for NSCLC (Sq+NSq; 4 Arms; 148 patients)
17 An Open-Label Single Arm Phase 2 Trial of Nivolumab with Ipilimumab as First-Line Therapy in Stage IV NSCLC Rios Perez Kloecker Schoenbachler Roberts Clark
18 Immune Checkpoint Inhibitors Should Have Efficacy Against Multiple Cancer Types * * * * *
19 Immune Checkpoint Inhibitors and Hematological Malignancies PubMed Search: immune checkpoint inhibitors and melanoma, 251 hits leukemia, 21 hits lymphoma, 45 hits myeloma, 10 hits
20 PD-L1 (B7-H1) Expression Correlates With Poor Survival in AML Chen et al. Clinical Significance of B7-H1 (PD-L1) Expression in Human Acute Leukemia. Cancer Biology & Therapy, 7:5, , 2008.
21 Anti-PD-L1 Suppresses AML in Mice Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood Aug 20;114(8):
22 On-Going Clinical Trials of Anti-PD1 in Hem Malignancies Sehgal, Whiteside and Boyidadzis. PD-1 Checkpoint Blockade in AML. Blood. Expert Opin Biol Ther, 15(8), , 2015.
23 First Anti-PD1 Trial for Hematological Malignancies
24 Response Characteristics and Changes in Tumor Burden in Patients with Hodgkin's Lymphoma Receiving Nivolumab. Ansell SM et al. N Engl J Med 2015;372:
25 A Study of Pembrolizumab (MK-3475) in Combination With Lenalidomide and Dexamethasone in Multiple Myeloma In the study with 50 heavily pre-treated patients, initial findings from 17 patients who were treated with KEYTRUDA (pembrolizumab) in combination with lenalidomide and low-dose dexamethasone demonstrated an ORR of 76 percent (n=13/17) (per IMWG 2006), including four very good partial responses (24%) and nine partial responses (53%). 57th American Society of Hematology Annual Meeting, 2015
26 Real Utility of Immune Checkpoint Inhibitors May Come From Combination Trials With CAR T Cells
27 Th17 Cells, Tregs and MDSCs Suppress T Cells Just Like Immune Checkpoint Proteins Th17 Treg MDSCs DC OFF 4 MHC/II MHC/I PDL1 TCR PD1 8 OFF PD1 TCR MHC/I Cancer PDL1
28 Th17 Cells, Tregs and MDSCs Suppress T Cells Th17 Treg MDSCs 4 8 TCR MHC/I Cancer
29 Th17 and MDSCs Require High Glycolysis Via Hypoxia Inducible Factor-1a (HIF-1a) and 6-Phosphofructo-2-Kinase Treg Th17 HIF-1a PFKFB3 Glycolysis MDSCs 4 TCR MHC/I 8 Cancer
30 Th17 Cell Differentiation and MDSC Immuno- Suppression (& PFKFB3) Require HIF-1a Th17 Differentiation MDSC T Cell Suppression PFKFB3 Expression Lewis Z. Shi et al. J Exp Med 2011;208: Cesar A. Corzo et al. J Exp Med 2010;207: Obach et al. JBC. 279,. 51, , 2004
31 PFK-158 Is A Potent and Specific Small Molecule Inhibitor of PFKFB3 PFK-158 = (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one Inhibition, IC 50 (mm) rec PFKFB3 Glucose Uptake F2,6BP Cell proliferation SPECIFICITY Does not inhibit enzymes involved in glycolysis including phosphoglucose isomerase (PGI), hexokinase (HK), or 6-phosphofructo-1-kinase (PFK-1) No cross-reactivity in a panel of 96 kinases (KinomeScan)
32 PFK-158 Is A Potent and Specific Small Molecule Inhibitor of PFKFB3 PFK-158 = (E)-1-(pyridyn-4-yl)-3-(7-(trifluoromethyl)quinolin-2-yl)-prop-2-en-1-one PFK158
33 Will Selective Inhibition of PFKFB3 With PFK-158 Attenuate the Immunosuppressive Functions of Th17 Cells and MDSCs? Treg Th17 MDSCs 4 TCR MHC/I 8 Cancer
34 Will Selective Inhibition of PFKFB3 With PFK-158 Attenuate the Immunosuppressive Functions of Th17 Cells and MDSCs? Treg Th17 PFK158 MDSCs 4 TCR MHC/I 8 Cancer
35 And Facilitate Activation of Cancer Immunity? Th17 PFK158 Treg MDSCs DC OFF 4 MHC/II MHC/I TCR TCR MHC/I 8 PDL1 PD1 OFF PD1 Cancer PDL1 Antigen Release
36 Th17 Cells and MDSCs Require PFKFB3 Differentiation of Th17 Cells: MDSC Function: T Cells +PFK mm 5 mm +MDSCs +MDSCs +MDSCs +acd3/cd28 +acd3/cd28 +acd3/cd28 +acd3/cd28
37 PFK-158 Depletes B16 Tumor Th17 Cells & MDSCs Vehicle +PFK-158 Th17 gdt17 IL-17 IL-17 CD4 IL-17 IL-17 CD4 60% 62% gdt gdt MDSC GR1 GR1 71% CD11b CD11b CD8 + /IFNg + IFN-g IFN-g 78% CD8 CD8
38 Combine PFK-158 With Anti-CTLA4? PFK158 Th17 Anti-CTLA4 Treg MDSCs DC OFF 4 MHC/II MHC/I TCR TCR MHC/I 8 PDL1 PD1 OFF PD1 Cancer PDL1 Antigen Release
39 PFK-158 Increases the Anti-Tumor Activity of Anti-CTLA4 Against B16 Melanoma
40 Phase 1 Safety Study of PFK-158 in Patients With Advanced Solid Malignancies James Graham Brown Cancer Center, University of Louisville Lombardi Comprehensive Cancer Center, Georgetown University MD Anderson Cancer Center UT Health Science Center at San Antonio Solid tumor patients who have failed at least one previous regimen 24 mg/m mg/m 2 delivered IV QOD x 3 weeks followed by 1 week rest repeated every 4 weeks until disease progression or high toxicity 27 patients enrolled > 18 patients completed 2 cycles thus far and were evaluated by diagnostic imaging after 2 months of treatment No drug-related SAEs 6/18 patients experienced clinical benefit
41 PFK-158 Depletes Th17 Cells & MDSCs in Patients % Baseline 0-50 Th17 gd-17 Treg MDSC % Baseline % Baseline PFK158 Dosing PFK158 Dosing PFK158 Dosing CD4+/ CD69+ CD8+ CD69+ CD8+ IFNγ+ CD8+CD27- CD28-CD57+ CD8+ CD137+
42 PFK-158 Markedly Increases Memory Effector CD8+ T Cells Healthy Donor Patient (Breast Ca) Pre-Dose C1D1 Post-PFK-158 C1D22 IFN-g IFN-g CD8 CD8 CD8 +PFK-158 x 3 Weeks
43 PFK-158 Depletes Th17 Cells & Activates CD8+ T Cells
44 PFK-158 Reduces PD-1 Expression in CD8+ T Cells PD % 6.5% 6.7% 5.9%
45 PFK-158: Clinical Benefits Of the 18 evaluable patients, 6 experienced clinical benefit: Patient Disease Status Ocular melanoma SD until Cycle Ser ovarian adenocarcinoma SD through Cycle Breast adenocarcinoma SD until Cycle Adenoid cystic carcinoma SD, in Cycle Renal cell carcinoma SD, in Cycle Pancreatic adenocarcinoma Until Cycle 2
46 Ocular Melanoma Patient CT scans (screening, end of Cycles 2, 4 and 6 ) showing an example of a liver met that became necrotic and regressed Ruth, A nthony K Total Tumor Mass (gm) 1000 P age: of IM :20 SE :6 P age: 1 9 of I M : 1 9 SE : PFK Observation Ipilimumab Months Pembrolizumab P age: 1 8 of I M : 1 8 SE : 7 P age: 1 5 of I M : 1 5 SE : 7
47 Ovarian Cancer Patient 02-01: CT scans confirmed peri-gastric tumor regression Longest diameter: 42 mm at screening, down to 39 and 26 mm at Cycles 2 and 4 respectively (38% decrease at Cycle 4) Product of perpendicular diameters: 1596 mm 2 at screening down 1044 and 546 mm 2 at Cycles 2 and 4 respectively (75% decrease at Cycle 4) + PFK PFK-158 Screening End of Cycle 2 End of Cycle 4
48 Breast Cancer Patient 01-10: Bony Mets: Stable Baseline Liver Mets: Necrotic Baseline +PFK158 +PFK158
49 Cardiophrenic nodule Renal Cell Carcinoma Patient 01-13: + PFK-158 Screening End of Cycle mm -- mm Right upper lobe lung nodule 10.8 mm 4.6 mm Diaphragmatic nodule 47.7 mm 26.7 mm Stable Disease: Cycle 8
50 Adenoid Cystic Carcinoma Patient 03-03: + PFK PFK-158 Stable Disease On-Going: Cycle 14
51 Pancreatic Cancer Patient 04-02: 70% decrease in CA19-9 levels after 1 cycle of PFK-158 Date Cycle CA19-9 9/8/15-66,121 9/28/15-167,050 11/2/15 C1D1 275,427 11/21/15 C1D19 83,166 12/11/15 C2D12 120,000 Increased bilirubin levels during Cycle 2 and restaged at Cycle 2..Multiple hepatic lesions, which now appear more cystic, the largest of which in segment II/III now measuring up to 11.7 cm X 9.0 cm X 7. 4 cm (previously 9.5 X 7.5 X 6.6 )
52 Pancreatic Cancer Patient 04-02: 70% decrease in CA19-9 levels after 1 cycle of PFK-158 Date Cycle CA19-9 9/8/15-66,121 9/28/15-167,050 11/2/15 C1D1 275,427 11/21/15 C1D19 83,166 12/11/15 C2D12 120,000 + PFK-158
53 Parent Compounds of PFK-158 (3PO+PFK15) Suppress Growth of Leukemia Cells HL-60 PML Cells HEL AML Cells Jurkat T-ALL Cells Clem et al. Molecular Cancer Therapeutics, 7(1):110-20, 2008 Clem et al. Molecular Cancer Therapeutics 12(8), 1-10, 2013 Reddy et al. Leukemia.26(3):481-9, 2012
54 Immune Checkpoint Inhibitors Are Going to Markedly Reduce the Annual Cancer-Related Death Rate Immune Checkpoint Inhibitors Have Clinical Activity In Multiple Solid Tumor Types & Certain Hematological Malignancies Responses Are Typically Durable With Clear Improvements in Overall Survival On-Going Immuno-Oncology Combination Trials Are Yielding Synergistic Increases in Clinical Activity Targeting Immunosuppressive Cells With Drugs Like PFK-158 May Be Able to Override the Cellular Immune Checkpoint and Increase the Activities of Anti-PD1 and Anti-CTLA4 in Hematological Malignancies
55 Key Collaborators in the Immuno-Oncology Program Division of Medical Oncology and Hematology Immunotherapeutics Miller Riley Sharma Mandadi Rojan Rios Redman Perez Kloecker Yaddanapudi Mitchell Brown Cancer Center Clinical Trials Office Schoenbachler Golladay Clark Smolenkov Ellis Roberts Radiology Coldwell Potts Van Meter BMT Tse Carter Hall Baum
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