Immunoterapia Pasiva y Activa en el Tratamiento de los Linfomas

Transcription

1 Immunoterapia Pasiva y Activa en el Tratamiento de los Linfomas Eduardo M. Sotomayor, MD Susan and John Sykes Endowed Chair, Professor, Department of Malignant Hematology Moffitt Cancer Center & Research Institute Effective July 1 st 2015: Cancer Center Director, George Washington University Washington, DC

2 Definition of Cancer Immunotherapy Strategies that utilize unmodified or genetically modified immune cells and/or their products (antibodies/cytokines) for cancer therapy

3 2013: Cancer Immunotherapy Science s Breakthrough of the Year

4 Cancer Immunotherapy: Timeline Nature Reviews Drug Discovery 10,

5 Types of Cancer Immunotherapy Passive Immunotherapy: Monoclonal antibodies Target cancer cells Adoptive cellular therapy (+/- engineered receptors: TCR or chimeric antigen receptor, (CAR) Active Immunotherapy Cytokines Cancer vaccines BI-specific T-cell Engaging antibodies Checkpoint blockade antibodies Modulate T-cell function

6 PASSIVE IMMUNOTHERAPY Monoclonal Antibodies for B-cell Lymphomas

7 Rituximab in B-cell Lymphomas 1997: Approval by the FDA of the first monoclonal antibody for the treatment of cancer (relapsed/refractory FL) Target CD20 expressed in B- lymphocytes

8 Rituximab: Things That We Know. 18 years later Addition of rituximab to chemotherapy: Increases ORR, CR, PFS, and OS in DLBCL Increases ORR, CR, PFS, OS in Follicular lymphoma Increases ORR, CR, PFS in MCL, SLL and other indolent lymphomas Rituximab maintenance after chemo-r induction: Prolongs PFS, FFS, without difference in OS in follicular lymphoma (PRIMA Study) Improves OS in elderly patients with MCL (Kluin- Nelemans et al. NEJM 367:520-31,2012)

9 Maintenance Rituximab in older patients with MCL 560 pts enrolled. CR rates similar with R- CHOP (34%) and R-FC (40%) BUT.with R-FC: more patient progressed, or died during the first remission and have significantly shorter OS. 274 patients that respond to chemo-r were randomized to maintenance with R or IFN-alpha (Kluin-Nelemans et al. NEJM 367:520-31,2012)

10 Rituximab: Things That We Know. 18 years later Rituximab maintenance after CHOP-R does not improve clinical outcomes in DLBCL Maintenance rituximab after R-induction is not superior to rituximab retreatment for TTTF (follicular lymphoma) (RESORT Study) But a planned subgroup analysis suggest that for non follicular subtypes (in particular Marginal zone lymphoma) maintenance R is superior than retreatment (TTTF: 3.74 y for R-maintenance vs. 1.07y for retreatment, p=.0002)

11 I. Novel anti-cd20 Antibodies

12 Novel Anti-CD20 Antibodies Type ADCC CDC LA-CD16 ORR PFS (mo) Ofatumumab I % 8.8 Ocrelizumab I 38% 11.4 Veltuzumab I % 6.2 Obinutuzumab II - 55% 11.3 AME-133v I - 50% - PRO I 27% -

13 II. Targets other than CD20

14 Anti-idiotype Galiximab CD19 B-cell Lumiliximab SGN-40 HCD122 Epratuzumab

15 Antibodies can be use to deliver localized radiation or toxins/drugs Radiation/ radionuclide Toxin/drug

16 Antibody-Drug Conjugate (ADC)

17 Elements of an Antibody-Drug Conjugate (ADC) Antibody specific for a tumor-associated antigen that has restricted expression on normal cells 1,2 Cytotoxic agent (payload) kills target cells when internalized and released 1,2 Linker attaches the cytotoxic agent to the antibody; newer linker systems are designed to be systemically stable and release the cytotoxic agent in targeted cells Carter PJ et al. Cancer J. 2008;14(3): Senter PD. Curr Opin Chem Biol. 2009;13(3): Polson AG et al. Cancer Res. 2009;69(6):

18 ADC: Mechanisms targeted delivery of a cytotoxic agent for the treatment of patients with B- cell malignancies Target cell Carter PJ et al. Cancer J. 2008;14(3):

19 Primary mechanism of action of ADCs: targeted delivery of a potent cytotoxic agent Cell Death Carter PJ et al. Cancer J. 2008;14(3):

20 Brentuximab Vedotin (Anti-CD30 MAb) Anti-CD30 MAb conjugated to monomethyl auristatin E (MMAE), a potent antitubulin agent CD30 expressing tumors: ALCL and HD Brentuximab Vedotin Mechanism of Action Brentuximab vedotin (SGN-35) ADC monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-cd30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released MMAE disrupts microtubule network G2/M cell cycle arrest Apoptosis

21 SGN-CD19A: anti-cd19-mc-mmaf maleimidocaproyl monomethyl auristatin F O N O O N O H N O N O O C H 3 N O O C H 3 N H O O H Humanized IgG1k isotype anti-cd19 antibody Conjugated to monomethyl auristatin F (MMAF) through the maleimidocaproyl linker An average of 4 MMAF molecules per antibody Preclinical data indicates the ADC mediates ADCC and ADCP, not CDC

22 Study Design A Continual Reassessment Method is used to estimate MTD Forero-Torres, A. et al, ASCO 2014

23 Best Change in Target Lesions * Greater than 100% increase 9 of 37 patients (24%) still on treatment Forero-Torres, A. et al, ASCO 2014

24 Case Study: 65-Year-Old Female with DLBCL Refractory to 3 prior therapies Extensive lung disease and PET-avid axillary adenopathy SGN-CD19A 4 mg/kg, on Cycle 5 of treatment Partial response at Cycle 2 (50% reduction) Further reduction at Cycle 4 with small PET-positive lesion present Grade 1 keratopathy stable on SGN-CD19A Baseline Cycle 4 Forero-Torres, A. et al, ASCO 2014

25 SGN-CD19A: Conclusions ORR 30% (11 of 37 patients) CR 16% (6 of 37 patients) SGN-CD19A is generally well tolerated No DLTs have been observed Superficial corneal changes and ocular symptoms managed with steroid eye drops and dose modifications Grade 3/4 anemia, thrombocytopenia, or neutropenia each observed in <10% of patients Encouraging antitumor activity with manageable toxicities enables novel combination regimens Forero-Torres, A. et al, ASCO 2014

26 Other ADC undergoing clinical evaluation Agent Coltuximab Ravtansine (SAR 3419) CD19 targeted Maytansinoid ORR Phase II R/R DLBCL Including primary refractory and double hit ORR:43.9% CR:14.6% Primary refractory: ORR:21.4% CR:7.1% Trneny et al. ASCO 2014 Inotuzumab Ozogamicin CD22 targeted Calicheamicin Phase II R/R DLBCL ORR: 33% CR:/CRu: 13% Advani et al Fayad et al

27 PASSIVE IMMUNOTHERAPY Monoclonal Antibodies for T-cell Lymphomas

28 Good news for patients with T-cell lymphomas: Several monoclonal antibodies targeting T-cell lymphomas CD4 CD25 CD52 CD30 CCR4 CD122 CD2 Tse E et al. Future Oncol. 2011;7(9):

29 PASSIVE IMMUNOTHERAPY Adoptive T-cell Therapy CAR T-cells

30 Why cellular therapy with T-cells? Tumor infiltrating lymphocytes (TIL s) harvested from resected tumors can be cultivated and activated ex-vivo and elicit clinical responses when reintroduced into the patient. The graft-versus-leukemia (GvL) immune response, mainly mediated by T-cells affords curative potential to stem cell transplant Adoptive transfer studies with TCR-engineered antigenspecific T-cells or T-cell clones provided proof of concept for this treatment modality T cells have a broader array of potential targets and have a potentially infinite half-life that is an advantage over biological moieties and small molecules.

31 Chimeric Antigen Receptor (CAR) T-cells Retrovirus or Lentivirus

32 CAR Generations Incorporation of additional costimulatory signaling domains with the goal of improving T-cell proliferation, cytotoxicity and cytokine production and augment T-cell resistance to apoptosis and improved in vivo persistence Maus MV et al. Blood Apr 24;123(17):

33 CAR T-cell Therapy 2-4 week process Kochenderfer JN & Rosenberg SA. Nat Rev Clin Oncol 10, , 2013

34 UPenn Group: Phase IIa Study of CTL019 CARs in Relapsed/refractory Lymphomas (ASH 2014) Enrollment: 26 patients evaluated (8 FL, 18 DLBCL) Single dose of 5x10 8 cells Schuster SJ, et.al. Blood. 2014;124:3087.

35 Phase IIa Study of CTL019 CARs in Relapsed/refractory Lymphomas Schuster et al. ASH 2014, Abstract 3087.

36 Phase IIa Study of CTL019 CARs in Relapsed/refractory Lymphomas: Responses Schuster et al. ASH 2014, Abstract 3087.

37 Follicular Lymphoma: /15/2014 CTL019: 11/04/ /03/2014

38 Double Hit Diffuse Large B Cell Lymphoma: /11/2014 CTL019: 07/22/ /19/2014

39 NCI Group: ASH 2014 Update CD19.CAR Leads to NHL Remissions and B Cell Aplasia Enrollment: 30 patients with relapsed/refractory DLBCL or FL (27 evaluable) Results: 22/27 patient achieved CR or PR 10 patients remain in ongoing CR of 1-37 months Low dose Cytoxan (60mg/m2) effective and better tolerated Mean peak absolute CAR + T Cells was 73 cells/ml in six patients tested Kochenderfer JA, et.al. Blood. 2014;124:550.

40 MSKCC Group: Phase I Study of 19-28z CARs after ASCT in R/R Lymphomas (ASH 2014) Enrollment: Relapsed/transformed FL (2), relapsed DLBCL (3), Transformed MZL (1) CARs delivered on days +2 and +3 after BEAM ASCT 5 received 5x10 6 CAR/kg, 1 received 10 7 CAR/kg Results: Analysis of first 6 patients 4/5 met criteria for non-severe CRS 2 patients >1yr post ASCT. All remain alive and in remission Sauter CS, et.al. Blood. 2014;124:677.

41 CAR T Cells: Side Effects Cytokine-release syndrome Encephalopathy B-cell aplasia Maude SL, et.al. NEJM. 2014;371(16):

42 ACTIVE IMMUNOTHERAPY Vaccines

43 Categories of Cancer Vaccines Antigen-specific Vaccines Tumor antigens have been identified and can be isolated to develop a molecularly defined vaccine Idiotype: B-cell lymphomas

44 Vaccination with Patient-Specific Tumor- Derived Antigen in First Remission Improves Disease-Free Survival in Follicular Lymphoma S. Schuster, S. Neelapu, B. Gause, J. Janik, F. Muggia, J. Gockerman, J. Winter, C. Flowers, D. Nikcevich, E.M. Sotomayor, D. McGaughey, E. Jaffe, E. Chong, C. Reynolds, D. Berry, C. F. Santos, M. Popa, A. Cord and L. Kwak J. Clin Oncol. 29 (20): , 2011

45 Phase III Vaccine Trial Id-KLH/GM-CSF n = 250 PACE chemo 2:1 Randomization LN Bx Assign CR KLH/GM-CSF Months n = 125 Inclusion Criteria: -Follicular lymphoma with surface IgG or IgM phenotype -Stage III or IV -Chemotherapy naïve - < 2 sites prior radiation treatment - > 2cm single lymph node accessible for biopsy

46 Phase III Trial of Idiotype Vaccine : DFS Idiotype vaccine Median DFS 44.2 mos Disease Free (%) Control vaccine 30.6 mos Log-rank P= Time (Months) Schuster et al. J. Clin Oncol. 29 (20): , 2011

47 Categories of Cancer Vaccines Tumor-cell based Vaccines Tumor antigens are unknown. Whole tumor cell as a source of multiple tumor-antigens (polyvalent vaccination). Tumor cells genetically modified to express immunologically-relevant molecules: Cytokines, chemokines, co-stimulatory molecules, adhesion molecules.

48 Moffitt Cancer Center: Universal GM-CSF producing and CD40L expressing bystander cells Human K562.GM-CSF.CD40L cell line Off the shelf / Ready to use

49 The GM.CD40L Bystander Radiation Tumor cell CD40L Confirmed by flow cytometry Apoptosis (FACS) GM.CD40L bystander cell GM-CSF Dendritic cell DC Precursor Confirmed by ELISA of supernatant

50 The GM.CD40L Bystander Activated T cells Activated Dendritic cell Lymph node (with resting T cells) Kill tumor cells

51 Phase II MCL Vaccine Trial Study design: Chemotherapy + Rituximab Vaccination in CR / PR / MRD Formulation: Autologous MCL cells (lymph node harvest) + Bystander GM.CD40L vaccine Endpoint: DFS, OS Immunological Endpoints Accrual: 43 patients

52 PFS According to Prior Treatment 1 Progression Free Survival De novo: Median PFS (95% CI): 13m (9,35) Relapsed: Median PFS (95% CI): 9m (2,14.5) Time From First Vaccine (months) Shah BD, et al. Manuscript under review

53 Overall Survival Overall Survival ~75% survival at 5 years Time From Diagnosis (months)

54 MCL Phase 2 Idiotype VaccineTrial (n=26) Long Term Follow-up T-cell Response 1 Median PFS Median OS 2 (11 year) 87% 24 months 8.7 years 1. Neelapu, et al. Nat. Med. 2005; 2.Grant, et al. ASH 2011

55 Phase I/II Ongoing Vaccine Trials Vaccination with CpG-Activated Whole Cell Vaccine Followed by Autologous "Immunotransplant" Vaccination with Dendritic Cell-Lymphoma Cell Hybrids and Dendritic Cells Pulsed With Tumor Lysates

56 Last 5 years -No further interest in lymphoma vaccines.. -Less funding for vaccine trials due to emergence of hot novel therapies (checkpoint blockade, targeted therapy)

57 Categories of Cancer Vaccines Next generation Cancer Vaccines Based on data emerging from next generation sequencing (NGS) of patient s tumor Identification of somatic mutations resulting in novel tumor antigens that can be recognized by T-cells

58 Cancer Vaccines: A paradigm shift

59 Categories of Cancer Vaccines Next generation Cancer Vaccines Phase I clinical trials to test a personalized cancer neoantigen vaccine have started (DFCI) Next steps include sequential combination with checkpoint blockade antibodies.. Vaccine first: To increase T-cell infiltrates to the tumor bed. IFN-gamma production leading to up-regulation of PD-L1 in tumor cells.. Anti-PD1 second

60 ACTIVE IMMUNOTHERAPY Bispecific Monoclonal Antibodies

61

62 BITE BITE antibody Blinatumomab FDA Approval on December 2014: Treatment of patients with Philadelphia chromosome (-) relapsed or refractory B-cell ALL (Ph. 2 Trial: CR:32%) Other BITE antibodies: Targeting CD20: Clinical studies ongoing for patients with relapsed/refractory CD20+ B-cell lymphomas

63 ACTIVE IMMUNOTHERAPY Checkpoint blockade antibodies

64 ASH 2014: The Years of Checkpoint Antibodies Anti-PD1, from solid tumors to hematologic malignancies.. -Pembrolizumab and Nivolumab, FDA approved for the treatment of patients with advanced melanoma and lung cancer. Anti-PD1 antibodies in relapsed/refractory Hodgkin s and Non-Hodgkin s Lymphomas

65 PD-1 PD-1 is a checkpoint protein expressed on T and B lymphocytes PD-1 interacts with its ligands (PD-L1 and PD-L2) to inhibit activation of T lymphocytes and anti-tumor immune response Human cancers can hijack the PD-1 pathway by up-regulating the expression of PD-L1 PD-1 blockade with MAbs may reactivate anti-tumor immunity Hamid, O et al SMR 2012

66 Releasing the breaks in T-cells by blocking PD1 with MAbs MHC T-cell receptor Tumor cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell T-cell Activation PD-1 PD-1 Receptor Blocking Antibody 73

67 Hodgkin s might be an ideal disease to block PD1/PDL1 interaction with MAbs Eosinophil Mast Cell Fibroblast HRS Cell CD4+ T H cell Malignant HRS cells make up only approximately 1% of the tumor in HL. The remainder of the tumor is comprised of various immune cells HRS cells closely interact with immune cells within the microenvironment in part through surface receptors CD8+ T C cell Granulocyte Frequent 9p24.1 amplification in HD with up-regulation of PD1 ligands CD4+ T Reg cell Küppers R. Nat Rev Cancer. 2009;9: HD is a suitable target to block PD1/PDL1 interaction 74

68 Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma Preliminary Safety, Efficacy and Biomarker Results of a Phase I Study Armand, P. et al, ASH 2014, Abstract 289 NEJM, December 6, 2014

69 Rationale and Design Based on likely vulnerability to PD-1 blockade, classical HL was included as independent expansion cohort in Phase 1b study of nivolumab in hematologic malignancies Relapsed or Refractory HM (N=105) Dose Escalation Cohort (n=13) 1mg/kg 3 mg/kg Weeks 1, 4 then q2 wks Key Inclusion Criteria: Age 18 years ECOG PS <2 Adequate bone marrow, renal and hepatic function Expansion dose selected on the basis of safety in dose-escalation cohort Dose Expansion Cohort (3mg/kg) Hodgkin Lymphoma (n=23) 3 mg/kg weeks 1, 4 then q2w until DP, CR or up to two years Non Hodgkin Lymphoma and Multiple Myeloma (n=82) Key Exclusion Criteria: Active or history of autoimmune disease History of CNS involvement Prior treatment with checkpoint blockade Prior organ or stem cell allografting chl, classical Hodgkin Lymphoma; HM, hematologic malignancy; wks, weeks; ECOG, Eastern Cooperative Oncology Group; CNS, central nervous system

70 Patients Characteristic N (%) Total 23 (100) Age 35 (20-54) chl histology Nodular sclerosis 22 (96) Mixed cellularity 1 (4) Prior ASCT 18 (78) Prior Brentuximab Vedotin 18 (78) Prior systemic therapies 2 to 3 8 (35) 4 to 5 7 (30) 6 8 (35)

71 Efficacy Total (N = 23) ASCT Failure Brentux Failure (n = 15) ASCT-Naïve Brentux Failure (n = 3) Brentux Naïve (n=5) (Prior ASCT n = 2, No prior ASCT n=3) Objective response rate 20 (87) 13 (87) 3 (100) 4 (80) 95% CI (66 97) (60 98) (29 100) (28 99) Best overall response 4 (17) 1 (7) 0 3 (60) CR PR 16 (70) 12 (80) 3 (100) 1 (20) SD 3 (13) 2 (13) 0 1 (20) 24-week PFS rate 86% 85% n/c 80%

72 Efficacy: Waterfall Plot ORR: 87% CR: 17% PR: 70% SD: 13% PD: 0%

73 Toxicity All AEs Related AE Grade 3 Related AE Grade 4 Related AE Discontinued for Related AE Patients, n (%) 22 (96) 18 (78) 5 (22) 0 (0) 2 (9) No drug-related deaths or drug-related grade 4 adverse events AEs leading to discontinuation: MDS (6 prior treatments including ASCT and RT) Grade 3 pancreatitis Other grade 3 related AEs: Increased lipase Pneumonitis Colitis Stomatitis Thrombocytopenia GI inflammation Lymphopenia Toxicity profile similar to that in solid tumors

74 Conclusions Nivolumab can be safely administered to patients with relapsed/refractory classical HL The preliminary efficacy results suggest a very high (87%) response rate in heavily pre-treated patients All tumors studied harbored genetic abnormalities leading to over-expression of PD-1 ligands Classical HL appears to be a tumor with genetically determined vulnerability to PD-1 blockade A Phase 2 study is ongoing Philippe Armand, et al, ASH 2014

75 Other anti-pd1 antibodies.. PD1 blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in patients with classical Hodgkin lymphoma after Brentuximab Vedotin failure: Preliminary results from a Phase 1b study ( KEYNOTE-013) Moskowitz, C.H. et al. ASH 2014, Abstract 290

76 Pembrolizumab in Hodgkin lymphoma 29 pts (median age: 32y) enrolled (20 pts:failed transplant, 8 pts: ineligible for transplant and 1 pt: refused transplant) Heavily pretreated patients (median of 4 prior therapies). All pts have failed brentuximab vedotin PDL1 expression in 100% of tumors Pembrolizumab given at 10 mg/kg IV every 2w until progression, toxicity or completion of 2 y of treatment Moskowitz, CH et al. ASH 2014

77 Pembrolizumab: Efficacy/Safety ORR: 66% (n=19) CR: 21% (n= 6 ) PR: 45% (n=13) SD: 21% (n= 6) PD: 14% (n= 4) Median time of response: 12 w Median DR: not reached 17 patients (89%) with ongoing responses Most common: Grade 1-2 respiratory events (20%) and thyroid (20%). Three pts. experienced four AE grade 3-4: Axillary pain, hypoxia, joint swelling and pneumonitis

78 Preliminary Results of a Phase I Study of Nivolumab in Patients With Relapsed or Refractory Lymphoid Malignancies Lesokhin et al. ASH 2014, Abstract 291

79 Nivolumab in R/R NHL: Study Schema Relapsed or Refractory HM (N=105) Dose Escalation Cohort (n=13) 1mg/kg 3 mg/kg Weeks 1, 4 then q2 wks Expansion dose selected on the basis of safety in dose-escalation cohort Dose Expansion Cohort (3mg/kg) Hodgkin Lymphoma (n=23) 3 mg/kg weeks 1, 4 then q2w until DP, CR or up to two years Non Hodgkin Lymphoma and Multiple Myeloma (n=82) Lesokhin et al. ASH Abstract 291.

80 Nivolumab in R/R NHL: Patients B Cell Lymphoma/PMBL (n = 31) T cell Lymphoma (n = 23) Characteristic, (N = 82*) FL (n = 10) DLBCL (n = 11) Other (n = 8) MF (n = 13) PTL (n = 5) Other (n = 3) MM (n = 27) Median age, y (range) 57 (37-69) 67 (37-74) 68 (61-74) 59 (30-78) 73 (47-81) 73 (51-76) 63 (32-81) Prior ASCT, n (%) 2 (20) 2 (18) (40) 0 15 (56) Prior therapies, n (%) 2 1 (10) 2 (18) 2 (25) 0 2 (40) 0 8 (30) 3 3 (30) 3 (27) 3 (38) 2 (15) 1 (20) 0 4 (15) 4 1 (10) 3 (27) 0 4 (31) 1 (20) 1 (33) 6 (22) 5 2 (20) 2 (18) 3 (38) 6 (46) 1 (20) 1 (33) 8 (30) *A single patient had CML. 2 patients had PMBL. 2 patients had other non-cutaneous T cell lymphomas (data not shown).

81 Nivolumab in R/R NHL: Efficacy Types n ORR, n (%) CR, n (%) PR, n (%) SD, n (%) B cell lymphoma 29 8 (28) 2 (7) 6 (21) 14 (48) DLBCL 11 4 (36) 1 (9) 3 (27) 3 (27) FL 10 4 (40) 1 (10) 3 (30) 6 (60) T cell lymphoma 23 4 (17) 0 4 (17) 10 (43) Mycosis fungoides 13 2 (15) 0 2 (15) 9 (69) PTCL 5 2 (40) 0 2 (40) 0 Multiple myeloma (67) Primary mediastinal B-cell lymphoma (100)

82 Nivolumab in R/R NHL: Tumor Analysis Tumor n Cytogenetics 9p alteration PD-L1+ by IHC DLBCL 6 1/6 1 FL 6 1/6 1/5* Other B cell lymphoma Mycosis fungoides PTCL T cell lymphoma Unknown 2 0 0

83 Nivolumab in R/R NHL: Summary Activity was demonstrated across multiple malignancies with ORRs of 40% and 36% in FL and DLBCL, respectively Nivolumab has a safety profile similar to that reported in other nivolumab trials Genetic alterations of 9p24.1 were uncommon in this small NHL series Multicenter, phase 2 studies are ongoing in DLBCL and FL Lesokhin et al. ASH Abstract 291.

84 All good news. but the tumor microenvironment is highly suppressive and tumor will eventually escape Is it possible to change this immunosuppresive microenvironment?

85 Changing the Tumor Microenvironment Decrease tumor burden Chemotherapy/ radiation Monoclonal Antibodies Decrease immunosuppresive mechanisms: Depletion of regulatory Tregs, MDSCs, suppressive macrophages Block regulatory check-points (Anti-CTLA4 antibodies, anti-pd1/pdl1 blocking antibodies Augment T-cell infiltration to the tumor bed: New vaccination strategies

86 The Future: Combination of immunotherapeutic agents IMIDs: Lenalidomide + Monoclonal Antibody: Rituximab Anti-PD1 + Brentuximab Vedotin in Hogdkin s disease New generation vaccines followed by checkpoint blockade

87 Sustained Remission With the Combination Biologic Doublet of Lenalidomide Plus Rituximab as Initial Treatment for Mantle Cell Lymphoma: A Multicenter Phase II Study Report Ruan et al., ASH 2014, Abstract 625

88 Frontline R 2 in MCL: Study Schema Mature findings from the first phase II multicenter study of R 2 as a chemotherapy-free initial treatment in previously untreated MCL Primary endpoint: ORR Secondary endpoints: safety, PFS, OS, QoL Previously untreated MCL (N = 38) Tumor mass 1.5 cm Low-intermediate risk MIPI; high-risk if ineligible for chemotherapy Adequate organ function Induction phase (N = 38) day cycles Lenalidomide: 20 mg/day*, days Rituximab: 375 mg/m 2 /week 4, cycle 1, then once every other cycle for 9 total doses Maintenance (n = 27) 28-day cycles beginning cycle 13 until PD Lenalidomide: 15 mg/day, days Rituximab: once every other cycle 23 patients remain on maintenance *Dose escalation of lenalidomide allowed to 25 mg/day if tolerated. Ruan et al. ASH Abstract 625.

89 Frontline R 2 in MCL: Summary Enrolled patients with demographics and disease features typical of MCL patients in need of therapy High proportion of patients achieved an ORR with this chemotherapy free induction regimen At median follow-up of 26 months: ORR = 89% (58% CR) 2-year PFS = 85% 2-year OS = 92% Results are reminiscent of studies using R 2 for upfront treatment of patients with Follicular lymphoma (Fowler et al) Ruan et al. ASH Abstract 625.

90 Immunotherapy of Lymphomas: Conclusions Exciting times for our field The initial success of monoclonal antibodies has been followed by new passive and active immunotherapeutic approaches (finally.) These new therapies when used as single agents have resulted in impressive responses in patients with relapsed/refractory disease However, deeper and more durable responses will be the results of rational combination of these new therapies Our generation might witness the CURE of all patients with HD (checkpoint antibodies, Brentuximab vedotin, chemotherapy) and more cures in NHL.

91 Thanks

92 Frontline R 2 in MCL: Efficacy Response ITT (N = 38) Evaluable (n = 36) ORR 84% 89% CR 55% 58% PR 29% 31% SD 5% 6% PD 5% 6% Median time to PR (range) 3 months (3-13) Median time to CR (range) 11 months (3-22) 24-month PFS (95% CI) 85% (67%-93%) Median follow-up time was 26 months (range, 5-38) Treatment was discontinued in 2 patients due to tumor flare without PD before tumor response evaluation Neither MIPI score nor Ki-67 index correlated with response QoL parameters were maintained or improved during treatment by FACT-Lym analysis Ruan et al. ASH Abstract 625.