VACUNAS TERAPÉUTICAS EN CÁNCER DE PULMÓN. Dr. DIEGO VENEGAS OJEDA Director

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2 VACUNAS TERAPÉUTICAS EN CÁNCER DE PULMÓN Dr. DIEGO VENEGAS OJEDA Director

3 Contexto actual El cáncer de pulmón es la causa más común de mortalidad por cáncer a nivel mundial 13% de todos los diagnósticos de cáncer cada año La mayoría de los pacientes con cáncer de pulmón son diagnosticados con la enfermedad avanzada (estadio IIIb / IV), la cirugía, la quimioterapia y la radioterapia son poco probable que resulte en la curación, aunque pueden mejorar significativamente la supervivencia y proporcionar alivio de los síntomas. Los pacientes con mutaciones genéticas específicas pueden beneficiarse de terapias dirigidas, como el erlotinib, afatinib, gefitinib, crizotinib, etc. La inmunoterapia activa resulta en beneficio para este gran subgrupo de pacientes.

4 Inmunoterapia en cáncer de pulmón Se consideraba un tipo de cáncer poco inmunogénico; sin embargo, hoy es un nuevo objetivo interesante de terapias inmunológicas. En marzo de 2015, la FDA aprobó el nivolumab inmunoterapia (Opdivo ) para el tratamiento de avanzado (metastásico) CPCNP escamoso que ha fracasado la quimioterapia. Esta aprobación se basó en los resultados de un ensayo de fase III que demostró que los pacientes que recibieron nivolumab vivieron, en promedio, 3,2 meses más que los pacientes que recibieron quimioterapia estándar. Esto se traduce en un 40% menor riesgo de muerte. Varios enfoques adicionales para la inmunoterapia para el cáncer de pulmón han demostrado ser prometedores en los primeros ensayos clínicos y han avanzado con el desarrollo de fase tardía. Estos tratamientos se pueden dividir en cuatro categorías principales: anticuerpos monoclonales, inhibidores de Check-points, vacunas terapéuticas y transferencia adoptiva de células T. Julie R. Brahmer and Drew M. Pardoll. Immune Checkpoint Inhibitors: Making Immunotherapy a Reality for the Treatment of Lung Cancer. Cancer Immunol Res; 1(2) August 2013

5 SV HITOS EN EL TRATAMIENTO DEL CANCER INMUNOTERAPIA TERAPIAS BLANCO RADIOTERAPIA Y QUIMIOTERAPIA CIRUGIA

6 PARADIGMA DE LA MEDICINA DE PRECISION GENES Efectivas inicialmente en etapas avanzadas, pero: Biomarcadores Drogas Especificas Rápida resistencia Tratamiento preciso Respuestas variables en diferentes tumores

7 RESISTENCIA Significativa pero transitoria respuesta de pacientes con melanoma al tratamiento con inhibidor B-Raf (vemurafenib) (Alexander Eggermont, IGR-France) Finn et al -BMC Medicine 2012

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9 COMPLEJIDAD: DIFERENTES VIAS DE ESCAPE FACILITAN LA RESISTENCIA

10 COMPLEJIDAD: DIFERENTES VIAS DE ESCAPE FACILITAN LA RESISTENCIA Cómo vencer la resistencia? 1. MAS DROGAS PARA NUEVOS BLANCOS 2. COMBINACIONES DE DROGAS 3. BIOPSIAS ITERATIVAS- TRATAMIENTOS CICLICOS 4. LA ESPERANZA: BIOPSIA LIQUIDA (ADN circulante ) 5.INMUNOTERAPIA

11 Slide 8 Presented By Pamela Kunz at 2014 ASCO Annual Meeting

12 Immunotherapy The Beginning of the End for Cancer:<br />Transforming Cancer into Chronic Disease ALL MELANOMA PATIENTS NOT ABLE TO RECEIVE B-RAF INHIBITORS, WILL BE PUT UNDER CHECKPOINTS INHIBITORS CHECKPOINTS INHIBITORS WILL SOON BECOME STANDARD TREATMENT FOR LUNG CANCER Presented By Laura Chow at 2014 ASCO Annual Meeting

13 La Inmunoterapia Por qué la Inmunoterapia es una alternativa? La Inmunoterapia consiste esencialmente en la estimulación del sistema inmune para atacar el tumor. Premisa básica de la Inmunoterapia: Relación entre el Sistema Inmune (SI) y el tumor El S.I puede reconocer los tumores y atacarlos Respuesta anti-tumoral El tumor ejerce un efecto supresor sobre el S.I cáncer = inmunopatología

14 Por qué Inmunoterapia? 1. FUNCIONA 2. GRAN REPERTORIO: diversidad molecular 3. SE PUEDE UTILIZAR A LARGO PLAZO 4. IMPACTO EN LA SUPERVIVENCIA, NO TR, NO SLP 5. NO TOXICIDADES ADICIONALES CON TRATAMIENTOS estándar contra el cáncer 6. Potenciación PROBABLE con quimioterapia y radioterapia 7. POTENCIAL DE EVOLUCIÓN junto con el tumor

15 Inmunoterapia del cáncer ACTIVA PASIVA ANTIGENO ESPECIFICO VACUNAS NO ANTIGENO ESPECIFICO -CITOQUINAS -INHIBIDORES CHECKPOINTS ANTICUERPOS MONOCLONALES -RITUXIMAB -TRASTUZUMAB -CETUXIMAB -NIMOTUZUMAB TRANSFERENCIA ADOPTIVA DE CELULAS - Cel. T -CAR (recept. Ag quim) -Cel. Dendriticas

16 Retos de la Inmunoterapia del cáncer Activar o reclutar un sistema inmune suprimido por la acción del tumor Activar o ruclutar un sistema inmune Senescente Ruptura de tolerancia a antígenos propios En el diseño de la Inmunoterapia y sus combinaciones es MUY importante: Selección del antígeno tumoral Selección del vehículo y/o adyuvante Selección del blanco en el S.I. Relevante para la fisiología del tumor Estimulación del sistema inmune innato para la presentación antigénica Activar activadores.. Inhibir inhibidores..

17 Anticuerpos monoclonales (cáncer pulmón) Nimotuzumab, mab IgG1 anti EGFR humanizado NSCLC, en combinación con Cisplatino y paclitaxel pegilado Fase III NSLC metastasico ( NCT ) Bavituximab, mab anti fosfatidilserina, fase III NSCLC no escamoso metastasico +/solo Docetaxel (SUNRISE; NCT ). Patritumab, mab anti HER3, en combinación con erlotinib, fase III NSCLC IIIb/IV ( NCT ). Rilotumumab, mab anti factor de crecimiento de hepatocitos (HGF), fase II / III NSCLC escamoso ( NCT ), fase I / II con erlotinib NSCLC recurrente o progresivo ( NCT ) Cixutumumab, un mab anti IGF-1R, fase II NSCLC ( NCT ). Cetuximab (Erbitux), un mab anti-egfr, fase II NSCLC IIIB en adyuvancia ( NCT ). IMMU-132, Inmunoconjugado mab-farmaco, hrs7-sn38, anti transductor señal de calcio asociado a tumor 2 (TROP2) metabolito Iritnotecan, Fase I / II NSCLC ( NCT ). Demcizumab, un mab anti ligando 4 dirigido (DLL4), activador de la vía de señalización Notch (Stem cell neoplasica - cancer), fase I / II pacientes SCLC no tratados en etapa extensiva ( NCT )

18 Inhibidores Checkpoint Anti CTLA4 El ipilimumab fase II más quimioterapia neoadyuvante ( NCT ). fase I más terapias dirigidas (erlotinib o crizotinib) en NSCLC metastasico con mutaciones de EGFR o ALK ( NCT ). Tremelimumab, fase II en pacientes con mesotelioma ( NCT ). Anticuerpos PD-1 Nivolumab fase III NSCLC IIIb/IV que progresan (CheckMate 153; NCT ). Fase II de nivolumab luego de azacitidina y entinostat ( NCT ). Fase I / II con o sin ipilimumab en pacientes con tumores sólidos avanzados o metastásicos, incluyendo SCLC ( NCT ). Pembrolizumab fase III NSCLC PD-L1-positivo ( NCT ). Fase II NSCLC con metástasis cerebrales ( NCT ). Fase II tumores con microsatélites inestables, NSCLC ( NCT ). Fase I / II combinación con quimioterapia o terapia dirigida para pacientes con NSCLC (MAGISTRAL-021; NCT ), Fase I / II en combinación con un inhibidor de IDO para pacientes con CPNM avanzado (MAGISTRAL-037; NCT ). Anticuerpos PD-L1 MPDL3280A Fase II NSCLC PD-L1-positivo, localmente avanzado o metastásico ( NCT ). MEDI4736, Fase II / III segunda línea NSCLC IIIB-IV ( NCT ). Fase II NSCLC localmente avanzado o metastásico ( NCT ).

19 Componentes de una vacuna de cáncer Antígeno Adyuvante Vehículo o sistema de depósito Inmunopotenciadores Células tumorales completas Antígenos tumor específicos o tumor asociados: - Proteínas recombinantes -Péptidos -Gangliósidos Sales minerales (Alúmina) Emulsiones aceite/agua (Montanide) Liposomas Virus Productos bacterianos (VSSP) Toxinas y lípidos Ácidos nucleicos (CpG) Citoquinas Células dendríticas Moduladorasmetabólicos Activación de Células B Activación de TCD8+) Activan a las células presentadoras de antígenos, y estas en consecuencia presentan los antígenos a las células T

20 Antígenos de vacunas terapéuticas en cáncer de pulmón NSCLC incluye antígenos tumorales específicos * EGFR (expresado 40-80% ) Data Monitor * MAGE-3 (expresado 42%) *NY-ESO-1(expresado 30% ) *P53 (mutado ~50 %) *Survivin *MUC. 20

21 Vacunas que han completado fases avanzadas de ensayo clínico (NSCLC) EGF vaccine (CIMAvax-EGF ) TG4010 vaccine Tergenpumatucel-L (HyperAcute ) Racotumumab (Vaxira ) MAGE-A3 Belagenpumatucel-L (Lucanix ) Tecemotide (Stimuvax ) Negative Results

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24 START: Overall Survival Delayed effect!!! Survival (%) L-BLP25 Placebo *2-sided, strata and multiplicity adjusted L-BLP25 (n = 829) Placebo (n = 410) Median OS, mos Adjusted HR Median follow-up, mos 0.88 (95% CI: ; P =.123*) Pts at Risk, n Mos Butts CA, et al. ASCO Abstract Used with permission. Placebo L-BLP

25 START: OS Analyses by Randomization Strata Beneficio en subgrupos Median OS, Mos L-BLP25 vs Placebo HR* (95% CI) Stage Stage IIIA (n = 487) 27.6 vs ( ) Stage IIIB (n = 752) 23.7 vs ( ) Region NA and Aus. (n = 321) 34.1 vs ( ) W. Europe (n = 475) 24.2 vs ( ) Rest of world (n = 443) 21.8 vs ( ) Response to chemo/rt SD (n = 396) Obj. response (n = 843) 20.4 vs vs ( ) 0.91 ( ) Chemo/ type RT Concurrent (n = 806) Sequential (n = 433) 30.8 vs vs ( ) 1.11 ( ) *Not adjusted for strata. Butts CA, et al. ASCO Abstract Used with permission Favors L-BLP Favors Placebo

26 Belangepumatucel-L Beneficio en subgrupos Belagenpumatucel-L is an allogeneic whole-cell vaccine constituted by four NSCLC cell lines (two adenocarcinoma, one SQCC, and one large cell carcinoma) that were transfected with a TGF-β2 antisense plasmid. Results of the Phase III Stop trial presented in ESMO Placebo-controlled, double-blind clinical trial. 532 stage IIIA, IIIB, and stage IV NSCLC who did not progress after first-line platinum-based chemotherapy, between 4 and 17.4 weeks from the end of frontline treatment. Median OS was 20.3 months with the study drug versus 17.8 months with placebo [hazard ratio (HR) 0.94, p=0.594]. Subgroup analysis revealed that patients randomized before 12 weeks after completion of frontline treatment had a median OS of 20.7 months with belagenpumatucel-l versus 13.4 months with placebo (HR 0.75, p=0.083). Patients with pre-treatment radiotherapy had a median OS of 40.1 months for belagenpumatucel-l versus 10.3 months for placebo, an important difference of 29.8 months (HR 0.45, p=0.014). Patients with stage IIIB/IV nonadenocarcinoma randomized within 12 weeks (n=99) had median OS of 19.9 months for belagenpumatucel-l versus 12.3 months for placebo (HR 0.55, p=0.036).

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29 Vaccine Company Patients Finished Biomarker/Predictor TG4010 Active immunotherapies in Phase III Development (NSCLC) Tergenpumatucel-L (HyperAcute) Racotumumab (Vaxira) Vacuna EGF (CIMAvax-EGF) Trangene (Novartis) New Link Genetic (company over 100 employees) CIM CIM Recombinant vaccinia virus of the Ankara strain (MVA) expressing the sequences of MUC1 and of the human IL-2. The product consists of 3 NSCLC cell lines that have been genetically modified to express alpha-gal carbohydrates on cell surface molecules Antiidiotype monoclonal antibody Racotumomab adsorbed on aluminum hydroxide (alum) gel as adjuvant Human recombinant EGF conjugated with a Neisseria meningitidis derived carrier protein. Hall RD; et.al. Cancer Control Jan;20(1):22-31 Iyendar P; et al. Cancer J. 2013,19: Melero I. Nature Reviews Clinical Oncology 11, , 2014 TIME: Global Phase 2b/3 trial evaluating TG4010 in combination with chemo in patients stage IV MUC-1 positive N: A randomized phase 2b/3 study of Tergenpumatucel-L immunotherapy vs docetaxel in progressive or relapsed NSCLC N:240 Trial Phase III evaluating CIMAvax-EGF in comparison with conventional treatment in advanced non-small cells lung N:1084 Trial Phase III evaluating CIMAvax-EGF in comparison with conventional treatment in advanced non-small cells lung N: 405 March 2019 July 2015 Triple positive (CD16+, CD56+, CD69+) circulating lymphocytes, and phenotype of activated NK cells No data 2019 In evaluation Finished Level antibody EGF, %pegfr inhibition, level EGF basal, Level IL8, number of CD4 T cells, number of CD8 T cells, Ratio CD4/CD8

30 Why cimavax would work?? Cimavax - EGF Mecanismo de acción diferente No es una clásica vacuna que intenta inducir respuesta de linfocitos T contra antígenos tumorales. Desarrolla el concepto de deprivación hormonal para tumores adictos al EGF

31 VACUNA CIMAVAX - EGF): Vacuna específica por el EGF CIMAVAX EGF: hu-rec EGF/ P64k/ Montanide ISA 51 VG EGF vaccine EGF EGFR Qué se persigue con esta vacuna? Blood concentration Time

32 La vacuna EGF induce altos títulos de anticuerpos que castran al EGF Clinical Trial % GAR (n, %) % SGAR (n, %) Geometric Mean Mean [EGF] Phase II CVV NSCLC n=67 Phase III CVV NSCLC n= 182 Vacine n=36 Control n=31 Vaccine n= 134 Control n= (52.8 %) 1 (2.8 %) 1: pg/ml 1 (3.2 %) 0 1: pg/ml 79 (59 %) 25 (18.7 %) 1: pg/ml 6 (11. 1 %) 0 1: pg/ml GAR good antibody responder (Ab titer >4000) SGAR good antibody responder (Ab titer >64000)

33 La vacuna EGF: beneficio clínico Phase II, NSCLC EGF Dose, 2.4 mg P<0.05 n= 260 Vaccine n= 176 Control n=84 MST (months) SV rate 12 months 52.3 % 40.2 % SV rate 24 months 30.7 % 19.6 %

34 Cimavax - Phase III Clinical Trial in patients with advanced NSCLC 405 patients 1:2 Randomization (Favoring Vaccine arm) 4 bi-weekly induction doses Monthly re-immunizations 2.4 mg of EGF per vaccination Patients older than 18 years with histologically or cytologically proven NSCLC at stages IIIB or IV were eligible. Random assignment was performed at least 28 days after completing first-line chemotherapy, but within 2 months. CIMAvax EGF 4 immunizations CIMAvax EGF Monthly re-immunizations All patients had measurable disease. At least stable disease after first-line chemotherapy (Cisplatinum+Vimblastine or Cisplatinum+Etoposide) Stage IIIb IV 1 st Line CT CY -3 days Best supportive care OOS TTP OR Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of at least 2, adequate bone marrow reserve, WBC count of at least 3,000/L, platelet count of at least 100,000/L, hemoglobin of at least 10 g/dl, life expectancy longer than 3 months, and normal creatinine, bilirubin, and transaminase values according to each institutional standards. Pregnancy or lactation, secondary malignancies, or history of hypersensitivity to foreign proteins rendered patients ineligible.

35 Vaccination with CIMAvax-EGF provide long-term survival advantage for a subpopulation of patients The effect of vaccinations on patient s survival benefit is observed in the planned per-protocol analysis (n=346) The five years OS rate is 23% for long-term vaccinated patients while for non-vaccinated patients is 8%. The conventional log-rank test show 2.13 month of OS benefit for vaccinated patients (logrank p= 0.040; HR % CI ).

36 Basal serum EGF concentrations as biomarker (threshold 900 pg/ml) Prognostic Biomarker Analysis (Control Group)

37 Cimavax Efficacy Análisis interino Fase III Cimavax

38 Seguridad Vacuna Cimavax EGF Long-term vaccination with CIMAvax-EGF is safe The 46% of patients received vaccinations during 12 months, 40% of patients received immunizations between 13 to 59 months and 14% of the patients received vaccinations moreover than 60 months. Summary of the more frequently treatment-related adverse events The more frequently treatment-related adverse events were injection-site pain, fever, headache, vomiting and shills ranging with grade 3 or 4 in proportions of 1.49% to 3.07% of all treatmentrelated adverse events.

39 CIMAVAX EGF: TENTATIVE SURROGATE BIOMARKERS OF CLINICAL RESPONSE Variable n Overall survival: median (months); 95% CI P value Antibody levels (M4) < 4000 (PAR) ( ) 0, (GAR) 85 19,9 (14,01-25,78) % pegfr inhibition (D76) < ,64 (24,62-29,51) 0, ,36 (-) EGF levels (M6) < 60 pg/ml 32 27,06 (22,76-31,37) 0, pg/ml 6 18,26 (14,54-21,98) Amphiregulin levels (M6) < 50 pg/ml 26 25,86 (14,47-37,26) 0, pg/ml 12 NR IL-8 concentration (M3) < 150 pg/ml 16 23,33 (9,28-37,38) 0,042 OD: optical density; NR: not reached 150 pg/ml 17 7,06 (4,82-9,30)

40 Vaccinated patients with serum Pre-treatment serum EGF as potential biomarker Control Group using a cutoff of serum EGF (870 pg/ml) EGF > 870 pg/ml Patients with high EGF had a worse survival as compared to patients with low EGF (logrank p=0.002; HR % CI ). 5 year SV rate: 11.5 % vs. 0 Patients with serum EGF>870 pg/ml had a better survival as compared to controls with the same EGF serum levels (logrank p= ; HR % CI ) 5 year SV rate: 21.3 % vs. 0 Strong evidences indicating that the benefits of the treatment with CIMAvax-EGF are limited to the high EGF subgroup Clinical Cancer Research 2015 (Manuscript CCR Submitted)

41 Senescence markers that could be predictive Proposed thresholds for number of CD4 T cells, number of CD8 T cells, Ratio CD4/CD8 as predictive markers of CIMAvaxEGF vaccination in NSCLC. Value n % HR Median Median Median p-value differences T Ctrl CD4+ >40 (pg/ml) CD8+CD28- <24(pg/ml) CD4/CD8 >

42 Cimavax in the current context Controls ITT Vaccinated ITT Maintenance Trials Vaccinated PP Equivalent to best switch maintenance drus Vaccinated High [EGFI 8.93 months months 12,43 months months

43 Chronicity: Two populations Two-component mixture model was applied to illustrate how immunotherapy impact the proportion of long term survival and/or the median of survival in both short- and long- term survival populations

44 Objectives Response to epidermal growth factor vaccine in patients with metastatic non small cell lung cancer (NSCLC) after progressing to first line therapy. Venegas, D - Neninger, E - Iberico, C - Oliva,C - Alarcon, A - Lozada, C - Galvez, J Gonzales,G Category: Developmental Therapeutics clinical Pharmacology and Immunotherapy. Poster Discussion Session ASCO Annual Meeting, Chicago Journal Clinical Oncology 30, 2012 (suppl; abstr 2531) PRESENTED BY: Diego Venegas Ojeda

45 Response to EGF vaccine in metastatic NSCLC after progressing to first line Objectives therapy. Describe the clinical features of patients with lung cancer non-small cell (NSCLC) treated with EGF Vaccine after progress to a first-line systemic treatment. Describe the immunological response by measuring serum titers of anti-egf. Describe tumor response by RECIST 1.1 Describe the overall survival and progression- free survival after vaccination Describe the adverse effects presented with the vaccine Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

46 Response to EGF vaccine in metastatic NSCLC after progressing to first line therapy. Methods Retrospective cohort. 12 patients diagnosed with lung cancer non-small cell that initiated treatment with EGF vaccine after progress to a first line systemic treatment since September 1, 2008 to December 31, centers: Hospital Nacional Cayetano Heredia, Clinica Anglo Americana, Peruvian Institute of Medical Sciences and Centro Neoplasico del Peru. They have completed at least 3 doses of EGF vaccine. They have consultations register at least 3 months follow-up after starting treatment with the vaccine if they are alive, if he died before it isn t necessary to fulfill this requirement Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

47 Response to EGF vaccine in metastatic NSCLC after progressing to first line therapy. Methods According to their performance status, clinical judgment and previous treatment, patients received 2 treatment schedule: 1. Chemotherapy Vaccine (Ch-V): After 29 days of the last chemotherapy, the patient received 1 dose of cyclophosphamide 200 mg/m2, 72 hours after receiving the 1 dose of anti EGF Vaccine. Patient received 4 applications in both deltoid and gluteal per dose and repeat every 15 days x 4 doses during the induction phase. He then goes to maintenance, he receives monthly applications until further deterioration of performance status. 2. Vaccine - Chemotherapy Vaccine (V-Ch-V): After 29 days of the last chemotherapy, the patient receives chemotherapy scheme similar to the vaccine schedule. However 21 days after the first dose continuous a line next chemotherapy, we were avoided in 48 hours receiving chemotherapy vaccine Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

48 Response to EGF vaccine in metastatic NSCLC after progressing to first line therapy. FEATURES PATIENTS FEATURES PATIENTS N =12 AGE Mean 56.5 y (42 79 y) SEX Male 8 (66.7%) Female 4 (33.3%) STATUS PERFORMANCE 0 5 (41.7%) 1 7 (58.3%) HISTOLOGY Adenocarcinoma 6 (50.0 %) Bronchioloalveolar 4 (33.3%) Adenosquamous 2 (16.7%) INITIAL CLINICAL STAGE I 1 ( 8.3 %) III 1 ( 8.3%) IV 10 (83.3%) THERAPY PREVIOUS Chemotherapy 12 (100.0%) Radiotherapy 6 ( 50.0%) Surgery 5 ( 41.7%) TIK EGFR 5 ( 41.7%) Antiangiogenic 3 ( 25.0%) Venegas D, et al. ASCO Abstract FEATURES PATIENTS N =12 N LINES SYSTEMIC THERAPY US PREVIO 1 2 (16.7%) 2 3 (25.0%) 3 2 (16.7%) 4 5 (41.7%) SITES OF METASTASIS Lung 5 (41.7%) Pleura 3 (25.0%) Brain 2 (16.7%) Extrathoracic lymph node 1 ( 8.3%) Kidney 1 ( 8.3%) COMORBILITIES Asthma 2 (16.7%) Hypothyroidism 2 ( 16.7%) Thyroid cancer 1 ( 8.3%) Depression 1 ( 8.3%) Single Kidney 1 ( 8.3%) Deep Venous Thrombosis 1 ( 8.3%) MODALITY THERAPY Ch V 6(50.0%) V Ch V 6(50.0%) N Vaccine Doses per patient (16.7%) (50.0%) 9 4 (33.3%) PRESENTED BY: Diego Venegas Ojeda

49 Response to EGF vaccine in metastatic NSCLC after progressing INMUNE to first RESPONSE line therapy. TO VACCINE INMUNE RESPONSE TO VACCINE 16.7% Good antibody responders 83.3% Poor antibody responders n= 12 patients Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

50 Response to EGF vaccine in metastatic NSCLC after progressing to CRITERIA first line therapy. RESPONSE CRITERIA RESPONSE RECIST % 8.3% 16.7% COMPLETE RESPONSE PARTIAL RESPONSE STABLE DISEASE 50.0% PROGRESSION DISEASE n= 12 patients Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

51 Response to EGF vaccine in metastatic NSCLC after progressing to first line therapy. OVERALL SURVIVAL AFTER VACCINE Median: months (CI 95%: m) Mean : months n = 12 patients Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

52 FREE PROGRESS SURVIVAL AFTER VACCINE Response to EGF vaccine in metastatic NSCLC after progressing to first line therapy. Median: 7.3 months (CI 95%: m) Mean : 9.49 months n = 12 patients Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

53 Ch + Vaccine vs Vaccine after progress first line Response to EGF vaccine in metastatic NSCLC after progressing to first line therapy. Median Overall survival: Ch V : 15.1 months (CI 95%: m) V Ch V: 19.8 months (CI 95%: m) Test Log Rank: 1.793; valor p = Median free progress survival: Ch V : 6.9 months (CI 95%: m) V Ch V: 7.3 months (CI 95%: m) Test Breslow: 0.65, valor p = Venegas D, et al. ASCO Abstract PRESENTED BY: Diego Venegas Ojeda

54 Response to EGF vaccine in metastatic NSCLC after progressing to first line Side therapy. effects SIDE EFFECTS FREQUENCY GRADE CTCAE 4.0 PERCENTAGE PAIN ON INJECTION SITE I II FEVER CHILLS ARTHRALGIA ERYTHEMA INDURATION MYALGIA HEADACHE NAUSEA/VOMITING ASTHENIA CELLULITIS CRAMPS RASH COUGH % No reported AE 82.7% Grade I 17,2% Grade II Venegas D, et al. ASCO Abstract 2531.

55 Response to EGF vaccine in metastatic NSCLC after progressing to first Conclusions line therapy. Vaccination anti EGF in patients with metastatic NSCLC after first line progress, alone or in combination with chemotherapy, was safe (no AE grade III or IV) and provoked an increase in anti-egf antibody titers (83.3% GARs). The Vaccine anti EGF produces clinical benefit (75%), improves overall survival (18.8 months) and progression free survival (7.3 months) Venegas D, et al. ASCO Abstract 2531.

56 Racotumomab Principio activo: Racotumomab, Anticuerpo monoclonal anti idiotipo murino Mab 1E10 (Ab2):IgG1 Adyuvante: Hidróxido de Aluminio precipitado Vaxira idiotypic Vaccine Technology NeuGcGM3Ab1 P3(IgM) Ab3 antigen specific AB3 Ab2 Raco(IgG1) Immunization RACO AB2 Racotumomab induces a specific citotoxic Ab3 (IgM and IgG) response against NeuGcGM3 (tumor associated ganglioside)

57 Racotumumab: Una vacuna anti-idiotípica NGcGM3 pre-immune hyper-immune J Immunol. 15;186(6):

58 Racotumumab ITT Per protocol 1.2 Funciones de supervivencia Supervivencia acum SVINC Grupo de Tratamiento B B-censurado A A-censurado 60 Log Rank p= Group Mean Median Vaccine (n=69) events=54 Placebo (n= 65) events:

59 Vacunas en desarrollo para cáncer de pulmón GV1001, que se enfoca en la htert (telomerasa humana transcriptasa inversa) de la subunidad de la telomerasa, que está altamente expresado en casi todos los tipos de cáncer, pero restringido en tejidos normales, está siendo probado en un estudio de fase III ( NCT ) para los pacientes con estadio III NSCLC inoperable. Tergenpumatucel-L (HyperAcute ) para los pacientes con estadio III o IV NSCLC, actualmente se está probando en un ensayo de fase II / III ( NCT ). Tergenpumatucel-L es una vacuna terapéutica que consiste en células de cáncer de pulmón humanos modificados genéticamente para incluir un gen de ratón para el cual el sistema inmune responde fuertemente. TG4010, que se enfoca en el antígeno MUC1, está siendo probado en una fase II / III ( NCT ) para los pacientes con CPCNP en estadio IV.

60 Vacunas en desarrollo para cáncer de pulmón Dribla (DPV-001), una vacuna hecha de nueve antígenos de cáncer más adyuvantes TLR, se está probando en un ensayo de fase II para pacientes con NSCLC en estadio III ( NCT ). MUC1 vacuna basada en péptidos para los pacientes con cualquier estadio del CPCNP se está probando actualmente en fase I / II de prueba ( NCT ). CV9202 vacuna contra el cáncer de origen RNActive, que consta de seis antígenos de cáncer diferentes, está siendo probado en un ensayo de fase I ( NCT ) para los pacientes con CPCNP en estadio IV. Antígeno WT1 vacuna está siendo probado en un ensayo de fase II ( NCT ) para los pacientes con mesotelioma después de completar la cirugía y la quimioterapia y / o radioterapia. TroVax, que dirige a la proteína 5T4 ampliamente encontrado en las células del mesotelioma, se está probando en un ensayo de fase II en pacientes con mesotelioma ( NCT )

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