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A Randomized Phase II Study of CSF-470 Therapeutic Vaccine Plus BCG Plus rhGM-CSF vs IFN-α2b in Cutaneous Melanoma Patie

This study evaluates the efficacy and safety of CSF-470 therapeutic vaccine in combination with BCG and rhGM-CSF compared to IFN-α2b in cutaneous melanoma patients. The study aims to assess overall survival, disease-free survival, distant metastasis-free survival, quality of life, and immune responses.

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A Randomized Phase II Study of CSF-470 Therapeutic Vaccine Plus BCG Plus rhGM-CSF vs IFN-α2b in Cutaneous Melanoma Patie

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  1. A randomizedPhase II study of theCSF-470 therapeuticvaccine plus BCG plus rhGM-CSF vs IFN-α2b in Cutaneous Melanoma patientsstages IIB, IIC and III María Marcela Barrio, PhD Centro de Investigaciones Oncológicas Fundación Cáncer (FUCA) Buenos Aires, Argentina

  2. Cancer Immunotherapy Strategies • Immunecheckpointmodulators (anti-CTLA-4, anti-PD-1/PD-L1 • mAbs) • Adoptivecell transfer (TILs, CAR T-cells) • Therapeutictargetedantibodies (i.e. trastuzumab, rituximab, • cetuximab) • Therapeuticvaccines

  3. CUTANEOUS MELANOMA – Clinicalstages IV (distant metastasis) III (lymph node metastasis) I (< 2 mm) II (> 2 mm) Stage Treatment Surgery Surgery Adjuvant IFN-alpha2b therapy Targeted therapy Immune checkpoint inhibitors Combinations Highriskpatients

  4. CSF-470 VACCINE Four gamma-irradiatedallogeneic melanoma celllines16x106/i.d (Apoptotic/Necroticcells) Therapeutic vaccination for cutaneous melanoma BCG + 106cfu/i.d + rhGM-CSF 100µg/day/fourdays /i.d.

  5. Previous Results Stage IIC and III • In a Phase I study vaccine was safe and well tolerated (4 doses, 3 weeks apart); Optimal rhGM-CSF dose was 400 µg; DTH response against tumor Ags; IgG2 but not IgG1 antitumor antibodies and median serum interleukin-12 was lower in progressing patients than in NED pts. All stage IV pts progressed. Predominant Th1 response triggered by the vaccination. (Barrio et al, J. Immunother 2006) • This mixture of allogeneic lethally irradiated melanoma cell lines (Apo-Nec) can be taken-up by DCs, induce their maturation, increase expression of CCR7 and cross present MART-1 and gp100 Ags to specific CTL clones to liberate IFN-ɣ. (Von Euw et al, J. Trans. Med., 2007). • In a Phase I study of DC/Apo-Nec vaccine the DTH score increased significantly in all pts after the first vaccination ( p < 0.05).; CD8+T cells specific to gp100 and MART-1 Ags were increased in some HLA-A*0201 patients after vaccination (ELISpot and tetramer staining); with a mean follow-up of 49.5 m, one stage IIC patient and 7/8 stage III patients remained NED but 7/7 stage IV patients have progressed.(Von Euw et al, J. Trans. Med., 2008).

  6. CASVAC-0401 Phase II/III Clinical study of CSF-470 plus BCG plus GM-CSF in stage IIB, IIC and III melanoma patients Phase II part of CASVAC-0401study InterimReportpresentedtotheArgentineRegulatory Authority (ANMAT) in 8/2014 and approved in 4/2015

  7. CASVAC-0401 Clinical study design

  8. Primary Outcome Measures • Security: measured according to the NCI-Common Toxicity Criteria • Efficacy: OS, DFS, DMFS, Partial or total remission (PR or CR) • Secondary Outcome Measures • Quality of Life (QOL): evaluated with EORTC QLQ-C30 questionnaire; ECOG Performance status • Induction of immune responses: Induction of immune responses associated to different vaccine doses for 2 years (Trial duration); Cellular immunity (DTH); PBMC analysis; Humoral immunity

  9. Elegibility InclusionCriteria: • Ages 18 -65 Years; both genders • Histologically confirmed cutaneous melanoma stages IIB, IIC or III (AJCC) • Non-detectable disease after surgery as asserted by CAT scans; pts with unknown primary melanoma allowed • Life expectancy > 6 months • Performance status (ECOG) 0 or 1 • Time post surgery ≤ 4 months • No chemotherapy, radiotherapy or any biological treatments prior to this study • CAT scans of brain, thorax, abdomen and pelvis in the 60 previous days to trial enrolling • Laboratory eligibility criteria include: hematocrit: ≥35 (hemoglobin > 10,5 gr %); WBC count > 3500/mm3, platelets > 100.000/mm3, total and direct bilirubin, serum oxalacetic transaminase and glutamic pyruvic transaminase < 1.5 fold the upper normal value; LDH ≤ 450 mU/ml; serum creatinine < 2.0 mg % • Negative serology for HIV, anti-HCV and HBsAg • All patients must give written informed consent Exclusion Criteria: • Pregnant or breast-feeding women • Diabetes (Type I or II) • Antecedents of psychiatric diseases • Evidence of active infections • Antecedents of viral or autoimmune hepatitis • Previous autoimmune diseases • Morbid obesity, defined as CMI >37 kg/m2 in women and >40 kg/m2 in men. • Other diseases that require regular treatment with corticoids or non steroids anti-inflammatory drugs

  10. (n=29)

  11. Characteristics of patients participating in CASVAC-04-01 study

  12. Adverse events CSF-470 + BCG + rhGM-CSF Arm

  13. Adverse events Interferon-α 2b arm

  14. QUALITY OF LIFE (QOL) Evaluated by EORTC QLQ-C30", versión 3.0 (European Organization for Research and Treatment of Cancer - Quality of Life Questionnaire) B A A- Score 1: higher value mean better QOL B- Score 2: lower value means better QOL Amongpatientsreceivingtreatment a significantlybetter QOL wasreported in the CSF-470 vaccinatedgroup vs IFN-α2b group

  15. DISTANT METASTASIS –FREE SURVIVAL (DMFS) (updated 3/2016) DMFS proportions at 25 months: 72.8 % CSF470 vs 27.2% IFN-α2b With a mean and maximum follow-up of 39.4 and 83 months respectively, a significant benefit in the distant metastasis-free survival for CSF-470 was observed (p=0.022, Gehan-Breslow-Wilcoxon Test).

  16. OVERALL SURVIVAL (OS) (updated 3/2016) Median OS IFN-α2b= 39 months CSF-470= notreached

  17. Delayed Type Hypersensitivity (DTH) On each vaccination, DTH reaction was measured by injecting a 1/10 dose of CSF-470 vaccine, without BCG or GM-CSF, in the forearm. The reaction was measured during four days. DTH intensity score (0): erythema < 0,5 cm; (1): macula 0,5-1,0 cm; (2): macula 1,1-2,0 cm; (3): macula > 2,0 cm and/or papule 0,5-1,5 cm; (4): papule > 1,5 cm. The DTH value is the sum of daily values for each patient, and the score reflects the intensity of the reaction. Values for NED (non-evident disease) and PRO (progressed) patients are shown. Vaccinated pts who remain disease-free had a higher DTH reaction than disease-progressed patients

  18. Histological analysis of CSF-470 vaccination site biopsy from patient #1 Edematous erythema , s.c nodule (lasting months) (A) granulomatous nodule distinguished a fibrosis zone (I), a highly vascularized zone(II),and a brisk-infiltrated with inflammatory cells zone(III). (B) Zone (II), in detail,showing lymphocytes and polymorphonuclear cells. (C) Zone (III) showing dense nested structures with a polynuclear cell (inset). D) Ziehl–Neelsen staining revealed absence of BCG bacilli in the vaccine site. (E) A positive control for bacilli staining is Shown (bowel tuberculosis). Bars 2mm (A); 50mm (B–E). Aris M et al, Front.Immunol. 6:144, 2015

  19. Immune profiling and MART-1 distribution in CSF-470 vaccination site biopsy Aris M et al, Front.Immunol. 6:144, 2015

  20. Analysis of CD11c+Ag-presenting cells in CSF-470vaccination site biopsy Aris M et al, Front.Immunol. 6:144, 2015

  21. PBMC Analysis PRE= previous to treatment POST 1= 6 months post-treatment C: PBMC immune populations gating strategy and results comparing PRE vs POST1 samples from CSF-470 and IFN-2b arms. CSF-470: NK PRE vs POST1 p=0.008; and Tregs PRE vs POST1 p=0.021. IFN-2b: CD3 PRE vs POST1 p=0.0036; CD4 PRE vs POST1 p=0.035; and CD8 PRE vs POST1=0.0075. For all comparisons, paired T test was used. ns= not significative.

  22. Biopsies from pt #006 Primary tumor (Pt#006) CD8 Dermic metastasis (25 months) CD8 Brisk CD8+T cellsinfiltration and in situ tumor cellcytolysis

  23. TCRβ repertoire in multiple samples obtained through CSF-470 vaccination from a CM patient (#006) from CASVAC-0401 who developed a cutaneous metastasis (Mts) at the end of the 2-year immunization protocol Methods: Genomic DNA was isolated from paraffin-embedded tumor tissues and from total PBMCs using RecoverAll (Ambion) & DNAzol (Invitrogen). DNA was verified by spectrophotometry (Nanodrop). High-throughput next-generation sequencing of the T-cell receptor beta (TCRβ) CDR3 region was performed at survey resolution and analyzed through Immunoseq platform (Adaptive Biotechnologies, USA). • Clonality index increased in peripheral blood TCRβ clones throughout immunization. Top Quartile is markedly higher in PBMC before immunization. 1/TQ Enrichment index revealed an oligoclonal repertoire of TIL. • Vaccination induced expansion of selected pre-immunization TCRβ clones, which might recognize dominant Ags either from patient´s tumor or the vaccine. • TCRβ clones arising after immunization might recognize dominant Ags from the vaccine or Ags derived by epitope spreading from the patient´s tumor. • More than 50% of total clones were detected only in MtsTIL suggesting local activation. However, most frequent MtsTIL clones included those that were expanded by CSF-470 vaccination. • TCRβ repertoire comparison allowed detection of some clones already reported in TIL from CM Mts and in memory repertoire against M.Bovis, possibly accounting for BCG adjuvancy. Dra. Mariana Aris (AACR 2016)

  24. Humoral Immune Response • Serum reactivity with melanoma cells components of CSF-470 - ELISA CSF-470 IFN-α2b • Serum reactivity with autologous melanoma cells (pt #006) ELISA IMMUNOFLUORESCENCE (1/10 dilution) Pre-vaccination 6 months post-vaccination Post1=6 m; Post 2=12 m; post 3=24m; F-UP= 24m

  25. Conclusions of CASVAC-04-01 phase II • CSF-470 vaccine + BCG + rhGM-CSF is safe and well tolerated; only one pt developed SAE (a grade 2 gastritis) possibly related to rhGM-CSF • DMFS in CSF-470 + BCG + rhGM-CSF vaccinated pts is significantly higher than in IFN-α2b treated pts (p= 0.022, max follow-up 83 months) • DFS and OS are still not significantly different between both groups. • CSF-470 + BCG + rhGM-CSF vaccination provides a significantly better QOL than IFN-α2b administration • CSF-470 + BCG + rhGM-CSF treated pts developed cellular and humoral immune responses. DTH reaction was significantly higher in NED vs PRO pts and a significant increase in NK lymphocytes was seen at 6 months post-treatment compared to baseline. All vaccinated patients developed antibody titers recognizing vaccine melanoma cells by 6 months of treatment that increased or remained stable during the study

  26. CSF-470 vaccine +BCG +GM-CSF model 2-IMMUNIZATION 1- GRAFT REJECTION Non- lymphoid tissue DCs Epidermis Missmatched HLA-I GM-CSF BCG “DANGER SIGNAL” CSF-470 Apoptotic/necrotic tumor cell Phagocytosis “VACCINE AS A GRAFT” Self HLA-I + Processed tumor peptides CD8 T cell Antibodies Lymph node Lymphocyte cross-presentation CD4 T cell CD8 infiltration? NK cells? Abs? Epitope spreading? Dendriticcell “GRAFT REJECTION” Tumor Ags release “MICROMETASTASES ELIMINATION/ CONTROL”

  27. Agencia Nac. Promoción Científica y Tecnológica (MINCYT) CONICET Instituto Nacional del Cáncer (MSP) Fundación Sales Fundación María Calderón de la Barca Fundación P. Mosoteguy Fundación Instituto Leloir (FIL) Nobeltri (CRO) CIO-Fundación Cáncer (FUCA) Paula Blanco María Betina Pampena Mariana Aris Ivana Tapia Gabriela Pizzurro Estrella Levy María Marcela Barrio José Mordoh Instituto Alexander Fleming Juan O´Connor Julio Kaplan Servicio de Hemoterapia Hospital Interzonal General de Agudos Eva Perón Alicia Inés Bravo Laboratorio Pablo Cassará Julio Vega María Teresa Manzolido Fernanda Quinteros

  28. Thank you !

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