MPDL3280A (anti-pd-l1) in metastatic bladder cancer. Powles T et al. Nature 515(7528), (2014)

Transcription

1 Combinations

2 MPDL3280A (anti-pd-l1) in metastatic bladder cancer Powles T et al. Nature 515(7528), (2014)

3 Targeted Therapy Any therapy that targets cancer s specific phenotype or genotype Specific immune generating therapy/vaccines T cell therapy Molecular targeted therapy

4 NCI Immunotherapy Agent Workshop Proceedings

5 Combinational Immunotherapy Vaccines Immune Modulators Immune Agonists Stimulatory cytokines (IL-2, IL-12, IL-15, TLR etc..) Co-stimulatory molecules (OX-40, GITR, 4-1BB) Immune inhibitors Check point inhibitors (CTLA4, PD1/PDL1, LAG3, TIM3, ido) Inhibitory cytokines/factors (IL-10, TGFb) Standard Therapy Chemotherapy Radiation Therapy Small Molecules T cell therapy/cars

6 Challenges What pre clinical data would be needed to move with the combination? Type of Combination/Schedule of combination Prediction of response What clinical trial design? Efficiency Time How to enable combinations from different developers pharm/bio Health Economics, financial adverse effect

7 Challenges What pre clinical data would be needed to move with the combination? Type of Combination/Schedule of combination Prediction of response Biology Activity in preclinical model OPTIMUM RESPONSE

8 Treg cell inhibitor-cyclophosphamide (CPM) Low Dose CPM selectively targets Treg cells, leaving other T cell populations intact (Lutsiak et al, Blood, 2005; Ikezawa et al, J Dermatol Sci, 2005). CPM Days TC-1 E7+aPD-1 E7+aPD-1 E7+aPD-1 Monitoring of tumor growth and survival

9 Vaccine/anti-PD-1/CPM combination induces potent antigen-specific immune responses in tumor bearing mice Days TC-1 tumor CPM E7+aPD-1 TERMINATION Number of IFNγ spots per 10 6 splenocytes *** *** *** *** 0 ***P<0.001 E7 E7 +apd-1 E7 +CPM E7 +apd-1 +CPM apd-1 +CPM NT

10 Vaccine/anti-PD-1/CPM combination induces potent antigen-specific immune responses in tumor bearing mice Number of IFNγ spots per 10 6 splenocytes ***P<0.001 E7 *** E7 +apd-1 Days TC-1 tumor *** E7 +CPM *** CPM *** E7 +apd-1 +CPM E7+aPD-1 apd-1 +CPM NT TERMINATION 100 Percent Survival Non-treated (n=15) E7 (n=14) apd-1 (n=15) CPM (n=15) E7+aPD-1 (n=15) E7+CPM (n=14) apd-1+cpm (n=15) E7 + apd-1 + CPM (n=20) Days after tumor implantation

11 Kaplan Meier Curves for Overall Survival and Progression-free Survival in the Intentionto-Treat Population. Hodi FS et al. N Engl J Med 2010;363:

12 Vaccines Peptides, polypeptides DND/RNA Viral Bacterial Administered Directly or on DCs

13 Vaccines % of MDSC in spleen * * * % of Treg within CD4 Tcells * * *

14 Combination of Lm-LLO-E7 with anti-pd-1 mab significantly improves therapeutic potency of immunotherapy Days TC-1 tumor Lm-LLO-E7 (5x10e6 CFU) +apd-1 mab (50ug) Monitoring of tumor growth Tumor Volume, cm 3 Days after tumor implantation Percent Survival Mkrtichyan et al., JITC 2013 Days after tumor implantation

15 Combinational Immunotherapy Vaccines Immune Modulators Immune Agonists Stimulatory cytokines (IL-2, IL-12, IL-15, TLR etc..) Co-stimulatory molecules (OX-40, GITR, 4-1BB) Immune inhibitors Check point inhibitors (CTLA4, PD1/PDL1, LAG3, TIM3, ido) Inhibitory cytokines/factors (IL-10, TGFb) Standard Therapy Chemotherapy Radiation Therapy Small Molecules CARS

16 Effects of PI3K-Akt pathway inhibition in Tregs vs. Tconv cells Stimulation TCR PTEN, SHIP-1 and -2 PIP2 PIP3 PIP3 PI3K P S473 Akt P T308 PDK-1 mtor P S6K1/2 S6 Proliferation

17 Effects of PI3K-Akt pathway inhibition on the TCR/IL2 Induced proliferation of Tregs vs. Tconv cells Stimulation TCR PTEN, SHIP-1 and -2 PIP2 PI3K TCN PIP3 Akt P S473 P T308 PIP3 PDK-1 WM mtor P S6K1/2 S6 Proliferation Abu Eid R.et al, CIR, 2014

18 PI3K-Akt inhibition enhances vaccine efficacy Spots per million E7 re-stim DMSO re-stim * P<0.05; ** P<0.01 * ** 50 0 No Vx UT DMSO WM TCN E7 Vx WM/TCN E7 Vx Collect splenocytes Abu Eid R.et al, CIR, 2014

19 Challenges What pre clinical data would be needed to move with the combination? Type of Combination/Schedule of combination Prediction of response Biology Activity in preclinical model OPTIMUM RESPONSE

20 Challenges What pre clinical data would be needed to move with the combination? Type of Combination/Schedule of combination Prediction of response What clinical trial design? Efficiency Time

21 Reviewed all cancer vaccine trials on PubMed Phase 1, phase1/2, and pilot studies in therapeutic cancer vaccines Reported from 1990 through 2011

22 What is the rate of vaccine-related toxicity in relation to the number of vaccinated patients?

23 Rahma et al, Clin Cancer Research, 2014

24 Rahma et al, Clin Cancer Res, 2014

25 What is the rate of vaccine-related toxicity in relation to the number administered vaccines?

26 Rahma et al, Clin Cancer Res, 2014

27 Rahma et al, Clin Cancer Res, 2014

28 Questions in Early Cancer Vaccine Development Does dose escalation determine MTD?

29 Rahma et al, Clin Cancer Res, 2014

30 Rahma et al, Clin Cancer Res, 2014

31 Trials with DLT Trial Vaccine Toxicity DLT Dols et al Allogeneic HER2/neu(+) breast cancer cells (SC) with GM-CSF or BCG Nausea/Vom iting 1 patient at 250 µg/m2 GM-CSF Maciag et al L. monocytogenes secreting HPV-16 E7 fused to Lm listeriolysin O (IV) Hypotension 3 patients at highest dose level Guthmann et al GM3 ganglioside with N. meningitidis outer membrane (IM) Hypotension 1 patient at highest dose level Rahma et al, Clin Cancer Res, 2014

32 Conclusion Dose escalation design has no role in defining The maximum tolerated dose (MTD) Except for bacterial vector vaccines

33 Questions in Early Cancer Vaccine Development Does dose escalation determine BAD?

34 Trials with Dose Related Cellular Vaccine Category Immune Response No. Trials Dose Related Cellular Immune Response Autologous 32 0 Allogeneic 4 0 Synthetic 80 0 Total Rahma et al, Clin Cancer Res, 2014

35 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Rahma et al, Clin Cancer Res, 2014

36 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Rahma et al, Clin Cancer Res, 2014

37 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Rahma et al, Clin Cancer Res, 2014

38 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Rahma et al, Clin Cancer Res, 2014

39 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Rahma et al, Clin Cancer Res, 2014

40 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Rahma et al, Clin Cancer Res, 2014

41 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Step 2. Combination Design Vaccine + X (X is an immune modulator, chemotherapy or targeted agent) X had no DLT X had a DLT X DLT is unknown Use the same dose Use the dose below MTD Proceed to traditional phase 1 Rahma et al, Clin Cancer Res, 2014

42 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Step 2. Combination Design Vaccine + X (X is an immune modulator, chemotherapy or targeted agent) X had no DLT X had a DLT X DLT is unknown Use the same dose Use the dose below MTD Proceed to traditional phase 1 Rahma et al, Clin Cancer Res, 2014

43 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Step 2. Combination Design Vaccine + X (X is an immune modulator, chemotherapy or targeted agent) X had no DLT X had a DLT X DLT is unknown Use the same dose Use the dose below MTD Proceed to traditional phase 1 Rahma et al, Clin Cancer Res, 2014

44 Alternative Clinical Trial Design For Combination Immune Therapy Step 1. Determining a starting dose of a vaccine Vaccine class and toxic (e.g., bacterial vector) Proceed to traditional phase 1 trial Vaccine class non-toxic (e.g., peptide) Vaccine class that is not used before & not expected to be toxic Use Immune Active Dose (IAD) from previous clinical trials One Patient Escalation Design (OPED) Step 2. Combination Design Vaccine + X (X is an immune modulator, chemotherapy or targeted agent) X had no DLT X had a DLT X DLT is unknown Use the same dose Use the dose below MTD Proceed to traditional phase 1 Rahma et al, Clin Cancer Res, 2014

45 Challenges What pre clinical data would be needed to move with the combination? Type of Combination/Schedule of combination Prediction of response What clinical trial design? Efficiency Time How to enable combinations from different developers pharm/bio

46 Challenges What pre clinical data would be needed to move with the combination? Type of Combination/Schedule of combination Prediction of response What clinical trial design? Efficiency Time How to enable combinations from different developers pharm/bio Health Economics, financial adverse effect