Is HLA a determinant of prognosis or therapeutic response to cytokines, IFN and anti-ctla4 blocking antibodies in melanoma? Helen Gogas, M.D. Ass. Professor in Medical Oncology 1st Department of Medicine, University of Athens, GREECE New York, September 2011 XV Perspectives in Melanoma Human leukocyte antigen (HLA) system HLA l h 6 t i HLA complex on chromosome 6 contains over 200 genes More than 40 of which encode leukocyte antigens The HLA genes that are involved in the immune response fall into two classes I and II, which are structurally and functionally different 1
Human leukocyte antigen (HLA) system II Class I genes are expressed by most somatic cells, although the level of expression varies depending on the tissue Class II genes are normally expressed by a subgroup of immune cells that includes B cells, activated t T cells, macrophages, dendritic d cells, and thymic epithelial cells In the presence of interferon-γ, other types of cells can express class II HLA molecules Human leukocyte antigen (HLA) system III The function of both class I and class II molecules is the presentation of short, pathogen derived peptides to T-cells, a process that initiates the adaptive immune response 2
Abnormalities of genes linked to the HLA complex Narcolepsy Hemochromatosis Infections diseases (eg malaria) Autoimmune diseases Genetic studies have shown that persons who have certain HLA alleles have a higher risk of specific autoimmune diseases than persons without these alleles Cancer Autoimmune diseases HLA-B27 HLA-DQA1*301 HLA-DQB1*302 HLA-DQ8 HLA-DR3 HLA-DR4 HLA-DR4 HLA-B51 HLA-DR3 HLA-DR3 HLA-DR11 HLA-DR4 HLA-DR3 HLA-Cw6 Ankylosing spondylitis Diabetes mellitus type I Rheumatoid arthritis Behcet s syndrome SLE Graves Hashimoto Postpartum thyroiditis Sicca syndrome Psoriasis 3
HLA and melanoma Susceptibility (conflicting data have been reported on HLA association and melanoma) Prognosis (relationship to disease recurrence) Linkage with prediction of response to treatment Susceptibility 4
No of patients Ethnicity HLA Reference 91 US Alabama DR4 Cancer Res, 1982 51 Italian A9, B35, Tumori, 1988 Cw4 146 NAC A11 Cancer Res, 1992 412 NAC B5, B8, B14, B15 J Immunother Emphasis Tumor Immunol, 1995 J Immunother, 1998 132 Italian DQB1*0501 J Immunother, 1998 DQB1*0301 53 Italian DQB1*0301 Tissue Antigens, 1998 0302, 0303 82 Spanish DR, DQ Acta Derm Venereol, 2002 Prognosis 5
No of patients Ethnicity HLA Reference 259 NAC DQB1*301 Cancer, 1996 591 NAC DRB1*1101 Annals of Surgical Oncology, 2002 1241 NAC DRB1*1101 Proc ASCO, 2007 382 Italian DRB1*01, DQB1*050, B*13, B*44, DRB1*04 212 Australian HLA-A2, B7, B35, B60 Tissue Antigens, 2004 Peter Hersey, Personal Communication Prediction 6
146 patients receiving undergoing IL-2 based immunotherapy. Significantly higher frequency of A11 phenotype among responders (40.5%) than in the melanoma patient population (20.5%; p<0.01), which was even more obvious among patients responding to TIL therapy (47.5% versus 22.1%; p<0.05). Association between DR4 haplotype and decreased tolerance to IL-2 among the patients receiving TILs (p=0.01). Cancer Res, 1992 54 patients receiving immunotherapy with IFNalpha and IL-2. Two HLA alleles Cw7 (p=0.014) and A1 (p=0.19) were observed more frequently in responding gpatients 272 patients receiving IL-2 based treatment. A correlation was noted between HLA-DR3 and DR4 alleles and decreased tolerance to IL-2, whereas homozygosity for HLA-DR decreased the chance of response. Melanoma Res, 1994 J Immunother Emphasis Tumor Immunol, 1995 7
82 patients treated with IL-2 based therapy. A statistically significant association between clinical response and the expression of HLA-DQ1 was observed (unadjusted p2=0.0017). HLA-DQ1 Was also independently associated with prolonged survival (p2=0.026). Ther Immunology, 1995 689 enrolled patients (294 vaccinated with allogeneic tumor vaccine and 259 observed). Among patients who matched two of the M5, the 97 vaccine treated patients had improved RFS compared with the 78 observation patients (5-year relapse-free survival, 83% vs 59%; p=0.0002). 0002) The major components of this effect were contributed by HLA-A2 and HLA-C3. Among those who were HLA-A2- positive and/or HLA-C3-positive, the 5-year RFS for vaccinated patients was 77%, compared with 64% for observation (p=0.004). This prospective analysis indicates a highly significant benefit of adjuvant therapy with Melacine among patients expressing two of the M5 class I antigens, validating a prior observation in stage IV disease. HLA-A2 and HLA- C3 contributed most to this effect. J Clin Oncol, 2002 8
INF and HLA 51 patients treated with high dose IFN-α2b and 54 patients treated with low dose in protocol E1690 Among patients t in the HLA-A2 A2 positive subset, IFNα2b treatment had a negative impact on RFS (p=0.02) compared with the OBS arm Among patients in the HLA-A2 negative subset, the RFS survival curves were the same as those reported for the largest experience in Trials E1690, E1684 and E1694 The test for interaction between treatment and HLA-A2 status was marginally significant (p=0.06) Cancer, 2002 Molecular HLA typing (Gogas, 2010) No allele was associated with absence of recurrence in patients receiving adjuvant interferon with the exception of HLA-Cw 06, an allele correlated with psoriasis. HLA-Cw 06-positive patients have better relapse-free and overall survival. 9
Relapse Results No of patients % No 127 44.7 Yes Deaths No 157 180 55.3 63.4 Yes Median follow-up 104 70.67 months 36.6 HLA-Cw Patients (%) Controls (%) No evidence Recurrence (%) Autoimmunity (%) (%) Cw*03 13.73 10.89 14.71 12.84 27.66 Cw*04 29.93 29.84 29.41 30.41 25.53 Cw*06 19.37 16.13 24.26 14.87 29.79 Cw*07 39.79 32.66 40.44 39.19 31.91 10
Cw*06 Median RFS Range 95% CI P-value Negative 35.7 1.09-115.2 18.3-53.1 Positive 100.3 2.66-100.31 62.7-137.9 0.020 Median Range 95% CI P-value OS Negative 76.53 2.33-85.93 60.7-92.4 0.017 Positive NRY 9.80-84.3 NE RFS plot by HLA-A2 status Survival Functions Probability of 0,8 0,6 0,4 0,2 0,0 f Relapse Free Survival1,0 HLAAx02 negative positive positivecensored negativecensored 0,00 20,00 40,00 60,00 80,00 100,00 Months from Start of Treatment 120,00 11
OS plot by HLA-A2 status Survival Functions y of Overall Survival Probability 1,0 0,8 0,6 0,4 0,2 HLAAx02 negative positive 0,0 0,00 25,00 50,00 75,00 100,00 125,00 Months from Start of Treatment RFS plot by Cw6 status Survival Functions Probability of 0,8 0,6 0,4 0,2 0,0 f Relapse Free Survival1,0 HLACx06 negative positive positivecensored negativecensored positivecensored negativecensored 0,00 20,00 40,00 60,00 80,00 100,00 Months from Start of Treatment 120,00 12
OS plot by Cw6 status Survival Functions y of Overall Survival Probability 1,0 0,8 0,6 0,4 0,2 HLACx06.00 1.00.00-censored 1.00-censored 0,0 0,00 25,00 50,00 75,00 100,00 125,00 SURV Questions Raised Do Cw*06 positive patients have slower growing Do Cw 06 positive patients have slower growing melanomas irrespective of IFN therapy? (Prognostic rather than a predictive factor?) 13
Retrospective Validation (collaboration with Prof. Dirk Schadendorf, in 279 melanomas) E1695 (Prof. J. Kirkwood) Prospective E1697 E1609 A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma Study MDX010-20 O Day, ODay, S. (2010). "A phase III, randomized, double-blind, blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma." ASCO Annual Meeting Abstracts J Clin Oncol 28:18s, 2010 (suppl; abstr 4) Hodi, F. S., O'Day, S. J. et al. (2010). "Improved Survival with Ipilimumab in Patients with Metastatic Melanoma." N Engl J Med. 14
MDX010-20: Patient Eligibility Inclusion Pre-treated stage III or IV melanoma HLA-A*0201 positive Pre-treated CNS metastases allowed Any LDH level Exclusion No autoimmune disease No prior therapy with anti-ctla-4 antibody No prior therapy with anti-cancer vaccine Ipilimumab and HLA Retrospective analysis of HLA subtype from 4 trials : Similar outcomes regardless of HLA-A*0201. Wolchok JD et al., 2010 15
Summary of phase II advanced melanoma trials used as data sources for pooled analysis and the comparator phase III study Study Population Treatment Regimen Reference CA 184-004/NC Pretreated t or Ipilimumab 3mg/kg (n=40) or 10mg/kg Schmidt et al 2009 T00261365 (phase II) untreated AM n=82 (n=42) Q3W x 4 then maintenance (Q12W) CA 184-022/ NC T00289640 (phase II) CA 184-008 / NC T00289627 (phase II) Pretreated AM N = 217 Pretreated AM N = 155 Ipilimumab 0.3 mg/kg (n=73), 3mg/kg (n=72) or 10 mg/kg (n=72) Q3W x 4 then maintenance (Q12w) Ipilimumab 10 mg/kg Q3W x 4 then maintenance (Q12W) Wolchok et al 2010 O Day et al. 1010 CA 184-007 / NC Pretreated or Ipilimumab 10mg/kg Q3W x 4 Weber et al 2009 T00135408 (phase II) untreated AM ±prophylactic budesonide (n =58) or N = 115 placebo (n=57) MDX010-020/ NC T0094653 (phase II) Pretreated AM n=676 (137 received ipilimumab alone) Ipilimumab 3 mg/kg Q3W x 4 ± gp100 vaccine, or vaccine only Hodi et al 2010 HLAA2*201 status and efficacy (survival, response, and disease control) across phase II trials versus the phase III study Ipilimumab Dose (study) HLA- A2*201 status (n) Median OS months 1-year Survival rate % 2-year Survival rate % Response BORR n (%) DCR N (%) 3mg/kg (CA 184-004/022) -(47) +(46) 8.74 10.1 39.0 45.0 18.4 31.5 2 (4.3) 3 (6.5) 11 (23,4) 15 (32.6) 10 mg/kg (CA 184-004/008/007/022) -(176) +(116) 14.3 8.48 54.1 41.3 32.7 28.5 20 (11.4) 9 (7.8) 51 (29.0) 33 (28.4) 0.3, 3 and 10 mg/kg (CA 184-004/008/007/022) -(266) +(187) 11.4 9.3 49.4 41.4 27.8 27.3 22 (8.3) 12 (6.4) 68 (25.6) 52 (27.8) 3 mg/kg (MDX010-020) +(137) 10.1 45.6 23.5 15(10.9) 39 (28.5) 16
Conclusions HLA-A2 does not predict for outcome in melanoma patients treated with IFN, ipilimumab, IL-2 or GM-CSF. Presence of HLA-Cw*6 is related with better outcome in IFNtreated t patients. t Its role needs to be investigated in populations treated with other cytokines. 17
Thank you 18