Immunotherapy in Oncology The New Era of Cancer Treatment

Transcription

1 Immunotherapy in Oncology The New Era of Cancer Treatment Trinh Pham, PharmD, BCOP Associate Clinical Professor University of Connecticut School of Pharmacy Statement of Disclosure I have no relevant financial relationships with commercial interests pertaining to the content presented in this program. 1

2 Objectives Explain the rationale for immunotherapy in oncology Describe the categories of immunotherapies currently available to treat cancer Discuss emerging data regarding the safety and efficacy of immunotherapeutic strategies for the treatment of melanoma and non small cell lung cancer (NSCLC) Discuss management plans for the most frequently occurring immune related adverse events Which of the following molecular processes is a strategy through which cancer can evade the immune system? A. Cancer cells produce antibodies against cytotoxic T lymphocyte antigen 4 (CTLA 4) B. Cancer cells decrease expression of TGF β and IL 10 C. Cancer cells increase expression of programmed death ligand 1 (PD L1) D. Cancer cells increase release of tumor antigens 2

3 Which of the following immunotherapy agent has FDA approved indication for melanoma, lung cancer, and renal cell cancer? A. IL 2 B. Ipilimumab C. Nivolumab D. Pembrolizumab Which of the following statements is TRUE regarding immune related adverse effects associated with checkpoint inhibitors? A. The AEs can rarely be managed by administering steroids and/or other immunosuppressive medication B. The most common AEs are neutropenia, bone pain, and fatigue C. May include opportunistic infection due to the inhibitory action of checkpoint inhibitors on the immune system D. The AEs are inflammatory toxicities that may be attributed to the activation and enhancement of the immune response triggered by checkpoint inhibitors 3

4 Immune related toxicities associated with immunotherapies are typically managed with: A. Steroids and other immunosuppressive agents B. Steroids and other immunosuppressive agents and/or treatment interruption C. Treatment discontinuation D. Treatment interruption Evade death signals that prevent proliferation of damaged cells Form new blood vessels Evade the immune system to avoid destruction Hallmarks of Cancer Change cellular metabolism to support proliferation Escape signals that limits cell replication to a finite number Evade signals that stop growth Invade tissues and spread throughout the body Hanahan D, Weinberg RA. Cell 2000;100(1):

5 The 3 Phases of Cancer Immunoediting Cancer cells are identified and destroyed by the innate and adaptive immunity The immune system is unable to completely eliminate all cancer cells but is able to control or prevent further outgrowth Immune system is unable to eliminate and control the outgrowth of the tumor because cancer cells have circumvented innate and adaptive immune system Dunn GP, Old LJ, Schreiber RD. Immunity; 2004: Cancer Immunity Cycle APCs stimulate priming and activation of cancer specific effector T cells in the lymph nodes. The balance between T effector and T regulatory cells is important in determining immune response to the cancer APCs present cancer specific antigens to T cells via MHC Class I and II T cells specifically recognize & bind to cancer cells through interaction b/n T cell receptors & antigen bound to MHC class I Destruction of cancer cells by innate immune system releases cell fragments that are recognized by antigens Releases additional tumor associated antigens to continue the cycle in step 1 Chen DS, Mellman I. Immunity; 2013;39:1 8 5

6 Mechanisms of Tumor Evasion from Immune System Loss of MHC antigens Dendritic cells and T cells treat tumor antigens as self T cells Inhibited from infiltrating the tumor immunosuppressive cytokines (TGF β, IL 10) inhibitors of T cell responses Galectin 1, indoleamine 2,3 dixoygenase (IDO) Suppression of proinflammatory danger signals impaired dendritic cell maturation Expression of inhibitory molecules (PD 1, PD L1) Lack of co stimulatory effectors (CD80, CD86) Dunn GP, Old LJ. Immunity 2004;21: Chen DS, Mellman I. Immunity; 2013;39:1 8 Rationale for Immunotherapy in Cancer risk of cancer in pa ents with suppressed immune function Cancer with tumor infiltra ng T cells have longer median overall survival and 5 year overall survival Boost or restore the ability of the immune system to detect and destroy cancer cells Overcome mechanisms by which tumors evade and suppress the immune response Adaptive immune response allows for specificity and long term memory which may result in durable responses 6

7 Therapies Affecting the Cancer-Immunity Cycle Immune Checkpoint Inhibitors Activating Costimulatory Receptors Cytokines Vaccines Chen DS, Mellman I. Immunity; 2013;39: Monoclonal Antibodies Checkpoint Inhibitors 3. Ipilimumab Nivolumab Pembrolizumab 2. IL 2 Cytokines Therapeutic Cancer Vaccines 4. Sipuleucel T 5. Adoptive T Cell Therapy 7

8 Cytokines Interleukin-2; IL-2 Aldesleukin (Proleukin ) 8

9 Mechanism of Action Endogenous glycoprotein that is formed and released during helper T cell activation Enhances natural killer cell and cytotoxic lymphocyte anti tumor killing FDA Approved Indications Metastatic renal cell carcinoma FDA approved 1992 Advanced metastatic melanoma FDA approved 1998 IL 2 for Advanced Melanoma and RCC Overall response rate 16 % for melanoma 15 % of RCC Durable response rate 6 10% Few relapses in patients with response > 2.5 years High degree of toxicity Contraindicated in patients with poor performance status, inadequate organ reserve, CNS involvement Requires treatment at institutions with relevant expertise in monitoring & management of IL 2 toxicities J for Immunotherapy of Cancer 2014;2:13 9

10 Infections Chills Rigors Constitutional Symptoms Nausea/vomiting GI Hypotension Cardiac Arrythmias Renal function Pulmonary Peripheral edema Neurotoxicity Dermatologic Metabolic Hepatic IL-2 Toxicities Gram Positive requires prophylactic antibiotics Chills and rigors occur 1 2 hrs after IL-2 Fever is common 2 4 hrs after IL-2 Muscle joint aches continuous and progressive during IL-2 treatment Not able to use corticosteroids as part of antiemetic regimen Epigastric distress, mucositis/stomatitis, diarrhea Blood pressure nadirs 4 6 hrs after each dose Sinus tachycardia, Supraventricular tachycardia, atrial fibrillation Oliguria Output, Rising creatinine Tachypnea/Dyspnea Expect to gain 5-10% body weight Delusions, visual hallucinations Rash, erythema, dry desquamation, pruritus Hypomagnesemia, hypocalcemia, hypokalemia, hypothyroidism Bilirubin (up to 10), Hepatic aminotransferases, Albumin (down to 1.8) Therapeutic Cancer Vaccines 10

11 Therapeutic Cancer Vaccines Increase presentation of tumor associated antigens (TAAs) to the immune system Increase activation of tumor specific T cells and B cells Many promising Phase II studies Phase III failure to show survival benefit Major categories: Whole cell vaccines Tumor antigen directed MAGEA3, MUC1 Cell based or protein/peptide or genetic Autologous or allogeneic Manipulated oncolytic virus T VEC Success of HPV/HBV vaccine for prevention Eligibility Evaluation for Sipuleucel-T: Castration resistant metastatic prostate cancer Minimally symptomatic or asymptomatic Neither chemotherapy or glucocorticoids within 28 days Patient s peripheral blood mononuclear cells + APCs & T cells are harvested Harvested cells cultured ex vivo with PA2024 (recombinant fusion protein composed of prostatic acid phosphatase (PAP) and GM-CSF Mature APCs reinfused into the patient to stimulate CD4+ and CD8+ cells triggering immune response against PAP + PC cells A complete treatment course: 3 doses administered at 2 weeks interval Each dose is manufactured 3 days prior to infusion 1 st infusion primes the anti tumor immune response Subsequent 2 infusions boost the response Mulders PF, et al. Cancer Immunology Immunotherapy 2015;64:

12 Sipuleucel-T Immunotherapy in mcrpc: Phase III IMPACT study Primary endpoint: overall survival Phase III IMPACT trial 512 men with mcrpc Randomized 2:1 to receive sipuleucel T or control infusion of non antigen treated APCs 22% reduction in risk of death 4.1 month prolongation in median overall survival compared to control 3 year survival = 31.7 % vs 23 % Kantoff et al. N Engl J Med. 2010; 363(5): Therapeutic Cancer Vaccines in Clinical Development Disis ML. Sem in Onc. 2014;41(supp5)s3 13 Class Name Description Clinical Development Tumor Cell DC/APC Algenpantucel L (HyperAcute, Newlink Genetics) Pancreatic tumor cell vaccine (GVAX, Aduro Biotech) Sipuleucel T (Provenge, Dendreon Corp) DCVAC/Pca Allogenic human pancreatic cancer vaccine GM CSF gene transfected tumor cell vaccine Autologous PBMC activated with PAP GM CSF Autologous DCs pulsed with killed prostate cancer line LNCAP Phase I: RCC, Prostate Phase II: Melanoma, NSCLC Phase III: Pancreatic Phase I: Multiple myeloma, melanoma Phase II: Pancreatic, AML, CML FDA approved for prostate cancer Phase II and III: prostate cancer AGS 003 DCVax L CVac GRNVAC1 ICT 107 Ovapuldencel T MelCancerVac DCP 001 BPX 201 Autologous DCs transfected with tumor and CD40L RNAs Autologous DCs pulsed with tumor lysate antigen Autologous DCs pulsed with MUC1 mannan fusion protein Autologous DCS transfected with htert and LAMP 1 Autologous DCs pulsed with antigens Autologous PBMCs in GM CSF Autologous DCs pulsed with allogeneic melanoma cell lysate Allogeneic dendritic progenitor cells (DCOne ) Autologous DCs engineered with DcCIDe technology to target prostate cancer cells Phase III: RCC Phase III: GBM Phase II: ovarian Phase II: AML Phase II:GBM Phase II: ovarian, peritoneal Phase II: CRC, NSCLC Phase II: AML Phase I: prostate 12

13 Therapeutic Cancer Vaccines in Clinical Development Disis ML. Sem in Onc. 2014;41(supp5)s3 13 Class Name Description Clinical Development Peptides /proteins GV1001 Nelipepimut S L BLP25 (Tecemotide) Rindopepimut POL 103 IMA901 MAGE A3 htert peptide HER2/neu peptide combined with GM CSF Liposome encapsulated synthetic peptide derived from MUC 1 hegfr variant III specific peptide conjugated to KLH Protein antigens from 3 melanoma cell lines with alum adjuvant Synthetic vaccine consisting of 10 diff TUMAPs MAGE A3 combined with GM CSF Phase I: Melanoma, pancreatic Phase II: HCC Phase III: NSCLC, pancreatic Phase III: Breast Phase II: NSCLC, rectal, CRC, multiple myeloma, prostate Phase III: NSCLC Phase II and III: GBM Phase III: melanoma Phase III: RCC Phase I: multiple myeloma Phase II bladder Phase III: melanoma PVX 410 IMA950 Multi peptide vaccine Multi peptide glioma vaccine containing TUMAPs Phase I: multiple myeloma Phase I and II: GBM Genetic Rilimogene CG0070 Recombinant fowlpox/vaccinia virus encoding hpsa and TRICOM Oncolytic adenovirus encoding GM CSF Phase I,II, III: prostate Phase II: bladder TG4010 Modified vaccinia human MUC1 and IL 2 Phase I: solid tumors Phase II: NSCLC Immune Checkpoint Inhibitors 13

14 Cytotoxic T Lymphocyte Associated Antigen 4 (CTLA 4) Immunologic Checkpoint 2 signals for T cell activation Postow MA. J Clin Oncol 2015;33:1-10 Programmed Cell Death Protein 1 and Ligand 1 (PD 1; PD L1) Immunologic Checkpoint CTLA 4 and PD 1 Blockade Pathway Nivolumab Pembrolizumab Ipilimumab Buchbinder EI, Desai A, Am J Clin Oncol 2015;9:1-9 14

15 Currently Approved Checkpoint Inhibitors Target Agent Class FDA Approved Indication CTLA 4 Ipilimumab IgG1, human 200 mg (5 mg/ml) Mar 2011 and Oct 2015 Melanoma: unresectable or metastatic melanoma adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy 50 mg (5 mg/ml) Phase III Clinical Trials of Ipilimumab in Metastatic Melanoma Hodi FS, et al. N Engl J Med 2010; 363(8): Robert C, et al. N Engl J Med 2010; 364(26):

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17 Currently Approved Checkpoint Inhibitors Target Agent Class FDA Approved Indication PD-1 (Programmed cell death protein 1) Nivolumab IgG4, human Dec 22, 2014 and Sep 30, 2015 Unresectable or Metastatic Melanoma: single agent as first line therapy or in patients with disease progression in combination with ipilimumab in patients with BRAF V600 wild-type melanoma March 4 (squamous) and October 9, 2015 Metastatic non-small cell lung cancer: in patients with progression on or after platinumbased chemotherapy. November 23, 2015 Advanced Renal Cell Carcinoma: of patients with advanced renal cell carcinoma who have received prior antiangiogenic therapy. Selected Trials of Nivolumab for Melanoma Nivolumab Monotherapy Melanoma Hodi et al. J Clin Oncol. 2014;32: abstr 9002 Ipilimumab naïve (n=107) ORR:34% 1,2,3 yr OS: 63%, 48%, 41% Median OS: 17.3 mos Med PFS: 3.7 mos Sznol et al. J Clin Oncol. 2014;32(suppl 5S):abstr LBA9003 Ipilimumab treated (n=33) Higher serum conc of ipi associated with higher RR to nivo Nivolumab Combination Therapy Nivo+ Ipi (concurrent) Sznol et al. J Clin Oncol. 2014;32(suppl 5S):abstr LBA9003 Nivo + ipi Sznol et al. J Clin Oncol. 2014;32(suppl 5S):abstr LBA9003 Ipilimumab naïve (N=53) 4 diff dose levels Ipilimumab naïve (N=107) (cohort 8: nivo 1 mg/kg + ipi 3 mg/kg) (N=40) ORR:31% ORR: 63% in PDL L1 positive ORR: 20% PD L1 negative 1 yr OS: 70% Median OS: 17.3 mos Med PFS: 3.7 mos ORR:42% 1, 2 yr OS: 85%, 79% Med OS: 40 mos Med PFS: 27 week ORR: 43% Med PFS: 37 wk Kim JW, Eder JP. Oncology (Williston Park).2014 Nov;28 Suppl 3:

18 Selected Trials of Nivolumab in Non Small Cell Lung Cancer (NSCLC) Nivolumab Monotherapy and Nivo Combination Therapy 3 mg/kg q 3 week Gettinger et al. J Clin Oncol. 2014;32:abstr 8024 Brahmer et al. J Clin Oncol. 2014;32(suppl 5S):abstr Nivo+ Platinum doublet Antonia et al. J Clin Oncol. 2014;32(suppl 5S):abstr 8113 Nivo + erlotinib Rizvi et al. J Clin Oncol. 2014;32:abstr 8022 Nivo+ipilimumab Antonia et al. J Clin Oncol. 2014;32(suppl 5S):abstr 8023 Chemo naïve, 1 st line (N=20) Heavily pre treated (n=129) 1 mg/kg q 2 week 3 mg/kg q 2 wk 10 mg/kg q 2 wk Chemo naïve, 1 st line (N=56); q 3 week cycle Gem/cis + nivo 10 mg/kg Pemetrexed/cis + Nivo 10mg/kg Paclitaxel/carbo + nivo 10 mg/kg or 5 mg/kg Chemo naïve, EGFR mutant (N=21) Chemo naïve, 1 st line (N=56) ORR:30% ORR 50% in PD L1 pos vs 0% in PD L1 neg ORR:17% 1, 3, 10 mg/kg: 3% v 24.3 vs 20.3% ORR ORR 15% in PD L1 pos vs 14% in PD L1 neg ORR:33% to 47% all 4 treatment arms Gem/cis + nivo 10 mg/kg: 33% Pemetrexed/cis + Nivo 10mg/kg: 47% Paclitaxel/carbo + nivo 10 mg/kg: 47% Paclitaxel/carbo + nivo 5 mg/kg: 43% ORR: 19% 1 patient w/no prior EGFR TKI had near CR ORR:16% Nivo 1 mg/kg +ipi 3 mg/kg: ORR: 11% in squamous, 13% in non squamous Nivo 3 mg/kg + ipi 1 mg/kg: ORR: 11% in squamous, 13% in non squamous Kim JW, Eder JP. Oncology (Williston Park).2014 Nov;28 Suppl 3:

19 Selected Trials of Nivolumab in Renal Cell Cancer Renal Cell Cancer Topalian et al. N Engl J Med. 2012;366: Motzer et al. J Clin Oncol. 2014;32(suppl 5S):abstr 5009 Previously treated (N=33) Previously treated (N=168) ORR: 27% PFS at 24 wk:56% ORR:20% Med OS: 0.3 mg/kg=18.2 mos 2 mg/kg=25.5 mos 10 mg/kg=24.7 mos Kim JW, Eder JP. Oncology (Williston Park).2014 Nov;28 Suppl 3: Currently Approved Checkpoint Inhibitors Target Agent Class FDA Approved Indication PD-1 Pembrolizumab IgG4, humanized September 4, 2014 Unresectable or Metastatic Melanoma: single agent in patients with disease progression Sep 4 (squamous) 2014 and October 2, 2015 Metastatic non-small cell lung cancer: whose tumors express PD-L1 as determined by an FDA-approved test and who have disease progression on or after platinum-containing chemotherapy. 19

20 Selected Trials of Pembrolizumab Melanoma Ribas et al. J Clin Oncol. 2014;32(suppl 5S):abstr LBA9000 Hamid etl al. J Clin Oncol. 2014;32 (suppl 5S):abstr Robert C, et al. Lancet.2014;384: NSCLC Rizvi et al. J Clin Oncol. 2014;32(suppl 5S):abstr 8007 Garon et al. J Clin Oncol. 2014;32(suppl 5S):abstr 8020 Ipilimumab naïve (IPI N) and treated (IPI T) (n=411) Ipilimumab naïve (IPI N) and treated (IPI T) (n=173) Ipilimumab refractory (n=103) Progression after > 2 ipilimumab doses Median F/U=8 months 88% of responders alive at time of analysis Chemo naïve, 1 st line PDL 1 positive (n=45) ORR:34% ORR in Ipi T:28% ORR in Ipi N: 40% 1 yr OS: 69% ORR: 33% vs 40% (2 vs 10 mg/kg) 1 yr OS: 72% vs 64% (2 vs 10 mg/kg) ORR: 26% (both arms 1 yr OS: 58% vs 63% (2 vs 10 mg/kg) ORR: 26% Med PFS: 22 vs 14 weeks in irrc: PFS survival 31 and 35 weeks (in favor of 2mg/kg) ORR:26% irrc: ORR 47%; durable Previously treated (n=194) ORR: 20% 23% in PD L1 positive 9% in PD L1 negative Kim JW, Eder JP. Oncology (Williston Park).2014 Nov;28 Suppl 3: Kim JW, Eder JP. Oncology (Williston Park).2014 Nov;28 Suppl 3:

21 Kim JW, Eder JP. Oncology (Williston Park).2014 Nov;28 Suppl 3: Evaluating Response with Immunotherapy Immune Related Response Criteria (irrc) Postow MA. J Clin Oncol 2015;33:

22 Immuno therapy Symptoms Immunotherapy Toxicities Skin GI Liver Endocrine Other Weber JS, et al. J Clin Oncol 2015;33(18): Ipilimumab Adverse Effects Semin in Oncol 37; 2010:

23 Villadolid J, Amin A. Transl Lung Cancer Res 2015;4(5): Tarhini A. Scientifica Volume 2013, Article ID , 19 pages / Kahler K. JDDG 2011;9: ; GiGiacomo AM, et al. Semin Oncol 2010;37:

24 Less Common irae Hematologic Hemolytic anemia, thrombocytopenia Cardiovascular Myocarditis, vasculitis, pericarditis Ocular Blepharitis, conjunctivitis, iritis, scleritis, uveitis Renal Nephritis Tarhini A. Scientifica Volume 2013, Article ID , 19 pages 24

25 Managing Immunotherapy AEs La-Beck N, et al. Pharmacotherapy 2015;35(10): Managing Immunotherapy AEs 25

26 Managing Immunotherapy AEs Grade 2 AE not responding within 3 days of corticosteroid therapy or relapse with taper La-Beck N, et al. Pharmacotherapy 2015;35(10): Adoptive T Cell Therapy 26

27 HLA Dependency Risk of offtumor ontarget toxicity HLA Restricted HLA Autologous Independent Highest Intermediate Safest Sensitivity Highest Lower High Clinical Feasibility Routine Routine Challenging Smith EL, Zamarin D, Lesokhin AM. Curr Opin Oncol 2014,26(6): CAR T Cells Extract a patient s T cells from the blood and modify them with viral vector to express a chimeric receptor specific for a particular TAA CD19 antigen expressed in B cell related cancers The engineered CAR T cells are expanded ex vivo then are reinfused back into the patient 27

28 Illustration of Approach to anti CD-19 CAR T-Cell Therapy Kochenderfer JN, Rosenberg SA. Nat Rev Clin Oncol 2013;10: Heiblig JM, et al. World J Stem Cells 2015;7:

29 Jena B. et al. Blood. 2010;116: Jena B. et al. Blood. 2010;116:

30 Heiblig JM, et al. World J Stem Cells 2015;7: Cytokine Release Syndrome (CRS) with CAR T Cell Therapy T cell activation results in severe inflammatory syndrome, vascular leak with possible multi organ failure High fevers, aches, hypotension, pulmonary edema, delirium Occurs within 1 14 days Severity proportional to tumor burden incite a stronger immune reaction Deaths have occurred in adults and children seem to be relatively resistant to severe CRS 30

31 Lee DW, et al. Blood 2014;124(2): Lee DW, et al. Blood 2014;124(2):

32 Lee DW, et al. Blood 2014;124(2): CTLA-4 PD-L1 Dendritic cell vaccine IL-2, IFN Immune Checkpoint Inhibitors Lymphocyte Activation Gene -3 (LAG-3) PD-L1 IDO Pathway T-cell Agonists (OXO, CD137, CD27) CAR-T cell Therapeutic vaccines Combination therapy 32

33 Gas On Tarhini A. Scientifica Volume 2013, Article ID , 19 pages Breaks Off Agent Target Company Immune Checkpoint Inhibitors MED14736 PD-L1 AZ/Medimmune Human IgG1 kappa MPDL3280A PD-L1 Roche IgG1 Tremelimumab CTLA-4 AZ/Medimmune INCB24360 IDO Incyte/Newlink T-cell Agonists, Co-Stimulator Urelumab (BMS66351) CD137 (4-1BB) BMS Human IgG4 enhance effector T-cells, NK-cell function in ADCC PF CD137 Pfizer Human IgG2 TNF superfamily Varilumab CD27 BMS Found NK, B, T cells. MED16383 OX40 AZMedimmune CP CD40 Pfizer Expressed on APCs, its ligand (CD40-L) expressed Dacetuzumab CD40 Seattle Genetics on T cells Lucatumumab CD40 Novartis Ligands BMS CD70 BMS Ligand for CD27. Expressed on RCC, NHL MGA271 B7-H3 Macrogenics 33

34 Future Direction for Immunotherapy Combination therapy Adjuvant therapy for early stage disease Indications for additional cancer diagnosis Many more immunotherapy agents with different mechanisms of action are in the pipeline Conclusion Immune therapies have activity in melanoma, lung, and renal cell cancer. Many ongoing studies in other tumor types Antitumor response is durable in some patients Response to immunotherapy occurs after initial increase in total volume Immune related adverse effects are different from traditional chemotherapy and treatment involves the use of immunosuppressive agent Many ongoing studies evaluating the optimal use of immune therapy in different cancers in different combination 34

35 Which of the following molecular processes is a strategy through which cancer can evade the immune system? A. Cancer cells produce antibodies against cytotoxic T lymphocyte antigen 4 (CTLA 4) B. Cancer cells decrease expression of TGF β and IL 10 C. Cancer cells increase expression of programmed death ligand 1 (PD L1) D. Cancer cells increase release of tumor antigens Which of the following immunotherapy agents has FDA approved indication for melanoma, lung cancer, and renal cell cancer? A. IL 2 B. Ipilimumab C. Nivolumab D. Pembrolizumab 35

36 Which of the following statements is TRUE regarding immune related adverse effects associated with checkpoint inhibitors? A. The AEs can rarely be managed by administering steroids and/or other immunosuppressive medication B. The most common AEs are neutropenia, bone pain, and fatigue C. May include opportunistic infection due to the inhibitory action of checkpoint inhibitors on the immune system D. The AEs are inflammatory toxicities that may be attributed to the activation and enhancement of the immune response triggered by checkpoint inhibitors Immune related toxicities associated with immunotherapies are typically managed with: A. Steroids and other immunosuppressive agents B. Steroids and other immunosuppressive agents and/or treatment interruption C. Treatment discontinuation D. Treatment interruption 36