INMUNO-ONCOLOGIA Estado actual y futuro Cáncer Renal, Melanoma, Cáncer de Pulmón y Medicina de Precisión Dr. Carlos Silva Hospital Británico de Buenos.

INMUNO-ONCOLOGIA Estado actual y futuro Cáncer Renal, Melanoma, Cáncer de Pulmón y Medicina de Precisión Dr. Carlos Silva Hospital Británico de Buenos Aires-Hospital Universitario Austral Universidad Católica Argentina

Declaración de Intereses
Doy o he dado conferencias convocado por: Astra Zéneca, Bristol Myers, MSD, Pfizer, Roche. Pertenezco o he pertenecido a Advisory Boards de Astra Zéneca, Bristol Myers, MSD, Pfizer, Roche. He percibido honorarios por estas actividades. No he sido ni soy medical advisor de ningún laboratorio. He asesorado al Ministerio de Salud de la República Argentina. He sido auditor de uno de los tres sistemas privados de salud más grandes de Argentina (SPM-Galeno).

Agenda Bases biológicas de la Inmuno Oncología
Impacto de la Inmuno Oncología en el tratamiento del cáncer Tratamiento del Cáncer Renal avanzado primera línea Tratamiento del Melanoma en Adyuvancia y enfermedad avanzada Tratamiento del Cáncer de Pulmón en segunda línea Biomarcadores Futuro no tan futuro

Metabolismo celular desregulado
Hoy encontramos 10 hitos fundamentales relacionados con la formación del cáncer Inhibidores vía EGFR Inhibidores quinasas dependiente ciclinas Señal proliferativa sostenida Evadiendo señales supresoras Inhibidores glicólisis aerobia Activación Inmune Anti CTLA4 Metabolismo celular desregulado Evadiendo inmunidad Pro-apoptóticos BH3 miméticos Resistencia muerte celular Pemitiendo Inmortalidad replicativa Inhibidores telomerasa Inestabilidad y mutación genómica Inflamación promovida por tumor Inhibidores PARP Drogas antiinflamat selectivas Inducción angiogénesis Activación Invasión y metástasis Inhibidores vía VEGF Inhibidores HGF/c-Met Hanahan & Weinberg. Cell 2011

¿QUE ES INMUNO-ONCOLOGĺA?
La Inmuno-Oncología comprende el desarrollo y utilización de nuevos componentes que aprovechan el sistema inmune del propio paciente para combatir el cáncer Impulsan las propiedades únicas del sistema inmune (especificidad, memoria, adaptabilidad, efectos sistémicos) Distintos de la cirugía, radioterapia, y modalidades citotóxicas/modalidades blanco que impactan al tumor Se ha identificado un número blancos terapéuticos basado en nuestra mejor comprensión del sistema inmune en el cáncer y los mecanismos que el tumor utiliza para evadirlo El objetivo es volcar el balance en favor de la inmunidad, llevando a la erradicación del tumor o la supresión por largo tiempo del crecimiento tumoral Tiene el potencial de proveer sobrevida durable y a largo témino con una buena calidad de vida para los pacientes con varios tumores sólidos y hematológicos Tiene el potencial de volverse una modalidad nueva e innovadora y los cimientos sobre los cuales construir nuevas estrategias de tratamiento Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6–viii9; De Vita VT, et al. N Engl J Med. 2012;366:2207–2214; Eggermont A. Ann Oncol. 2012;23 Suppl 8:viii53–viii57.

Somatic Mutations May Give Rise to Patient-Specific Tumor Neoantigens
Presented By Leisha Emens at 2015 ASCO Annual Meeting

ACTIVACIÓN DE LINFOCITOS T CITOTÓXICOS
MODELO DE LAS TRES SEÑALES

MDX010-20: 1- and 2-Year Survival Rates, OS1
Survival Rate Median OS, mo 1 Year 2 Year (95%CI) Ipi + gp100 44% 22% 10.0 (8.5, 11.5) Ipi + pbo 46% 24% 10.1 (8.0, 13.8) gp100 + pbo 25% 14% 6.4 (5.5, 8.7) 1.0 0.8 0.6 0.4 0.2 0.0 Proportion alive Years Patients at risk Ipi + gp Ipi + pbo Gp100 + pbo 1. Hodi FS, et al. N Engl J Med 2010;363: 13

Ipilimumab: Association of Response With Survival in Melanoma
1.0 0.9 0.8 0.7 0.6 Proportion Alive 0.5 0.4 CR, complete response; irPR, immune-related partial response; irRC, immune-related response criteria; irSD, immune-related stable disease; PD, progressive disease; PR, partial response; SD, stable disease; WHO, World Health Organization. It is clear that patients who are treated with ipilimumab and have a response—a clinical response—will have an association of response with survival. As shown in this slide, patients who exhibit a progressive disease have a very shortened survival, as shown by the green line and stars, whereas patients who had either a partial response or a complete response by standard criteria clearly have substantially improved survival. 0.3 0.2 CR/PR/SD (by WHO criteria) irPR/irSD (by the irRC) PD and unknown response 0.1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Mos Wolchok JD, et al. Clin Cancer Res. 2009;15:

Consistent Survival Benefit in Subpopulations1 Pre-specified Subgroups in MDX010-20
Favors: Ipi + gp100 gp100 Ipi gp100 ALL PATIENTS Gender Male Female Age < 65 years ≥ 65 years Female < 50 years Female ≥ 50 years M-stage at Study Entry M0, M1A, M1B M1C Baseline LDH ≤ ULN > ULN ≤ 2x ULN > 2x ULN Prior Use of IL-2 Yes No 1. Hodi FS, et al. N Engl J Med 2010;363: Hazard Ratio and 95% CI

3-year OS Rate (95% CI): 22% (20% to 24%)
Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma 1.0 0.9 0.8 N = 1861 Median OS (95% CI): 11.4 mo ( ) 3-year OS Rate (95% CI): 22% (20% to 24%) 0.7 0.6 Proportion Alive 0.5 0.4 0.3 CI, confidence interval; OS, overall survival. 0.2 0.1 Ipilimumab CENSORED 0.0 12 24 36 48 60 72 84 96 108 120 Months Patients at Risk Ipilimumab 1861 839 370 254 192 170 120 26 15 5 Hodi S, et al European Cancer Congress. Abstract LBA 24.

Nivolumab: Duration of Response
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Med., mo. (95%CI) NSCLC (n=22) (9.7 - NE) Melanoma (n=33) ( NE) RCC (n=10) ( NE) Censored Proportion progression-free MEL, melanoma; NSCLC, non-small cell lung cancer; NE, not estimable; RCC, renal cell carcinoma. Months since initiation of response No. at Risk NSCLC MEL RCC Topalian SL, et al. ASCO Abstract 3002.

Ways to enhance T cell attack
Presented By Michael Postow at 2017 ASCO Annual Meeting

PERSPECTIVAS DE LA INMUNOTERAPIA PARA EL CÁNCER
Targeting regulatory T cells: • Depleting (Denileukin diftitox, CD25-specific antibody, cyclophosphamide) • Blocking trafficking (CCL22-specific antibody) • Blocking differentiation and signalling (blocking FOXP3 signal) Targeting suppressive molecules: • Blocking suppressive molecules (B7-H1, B7-H4, IDO, arginase) on APCs • Blocking suppressive molecules (CTLA4, PD1) on T cells • Blocking soluble suppressive molecules (TGFβ, IL-10, VEGF, COX2 • Surgical debulking • Radiation therapy • Chemotherapy • Anti-angiogenic therapy • Tumour-associated antigens (tumour peptides) • APC vaccination (dendritic cells) • Adoptive T-cell transfusion (effector T cells) • Cytokine and/or chemokine administration (IL-7, IL-15 and IL-21) Human tumour Combinatorial therapy Traditional tumour therapy Novel tumour immunotherapy Conventional Weiping Zou Nat Rev. Immunol. 6:

¿Todos los pacientes deben ser tratados de inicio?

Treatment Patterns: Untreated Patients
In a large prospective cohort of mRCC patients, median time to treatment initiation was 7.2 months, and 20% of patients remained untreated at 4 years Initiation of therapy within: N=920 6 months 47% 1 year 57% 2 years 68% 3 years 74% 4 years 80% 5 years 83% Factors predicting later initiation of targeted therapy: History of radiation therapy Older age at time of metastatic disease Presence of brain metastases only Presence of bone metastases Indolent disease High number of metastatic sites . Bains P et al. Poster presentation at ASCO GU

¿Cuál es la evidencia de la efectividad de la inmunoterapia para frenar la enfermedad?

Long-Term Overall Survival With Nivolumab in Patients With mRCC
1.0 0.9 Median OS, months (95% CI) Nivolumab 22.4 (12.5–NE) 0.8 0.7 0.6 Overall Survival (Probability) 0.5 38% 0.4 34% 0.3 0.2 0.1 0.0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 Months Number of patients at risk Nivolumab 34 28 24 18 14 13 12 11 8 6 2 1 In CheckMate 003, minimum follow-up was 50.5 months . McDermott DF et al. Oral presentation at ASCO

CA /CheckMate 025 Phase III, randomized, open-label trial of nivolumab vs everolimus in subjects with advanced or metastatic clear cell RCC who have received prior antiangiogenic therapy1 N=822 Key Inclusion Criteria Advanced/metastatic clear cell RCC No more than 3 total prior regimens in advanced/metastatic setting 1 or 2 prior antiangiogenic therapy regimens in advanced/metastatic setting Karnofsky PS ≥70% No CNS metastases No prior therapy with mTOR inhibitor No autoimmune disease Nivolumab 3 mg/kg IV q2w Until progression*, unacceptable toxicity, withdrawal of consent, or end of trial R 1:1 Everolimus 10 mg PO qd Start Date: September 2012 Estimated Trial Completion Date: September 2016 Estimated Primary Completion Date: May 2015 Status: Ongoing but not recruiting Trial Director: Bristol-Myers Squibb Primary Outcome Measure: OS Secondary Outcome Measures: PFS, ORR, duration of objective response, duration of OS by PD-L1 status, safety, disease-related symptom progression rate * Patients may continue treatment beyond progression (RECIST 1.1) if investigator-assessed clinical benefit is achieved and treatment is well-tolerated.2 Clinicaltrials.gov. NCT Accessed on October 2, 2015. CA clinical protocol. August 27, 2014.

OS in Patients With mRCC
Median OS was 25 months and 19.6 months in the nivolumab and everolimus groups, respectively Median OS, months (95% CI) Nivolumab 25.0 (21.8–NE) Everolimus 19.6 (17.6–23.1) 1.0 0.9 0.8 0.7 0.6 Nivolumab 0.5 Overall Survival (Probability) 0.4 Everolimus 0.3 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 Months # of patients at risk Nivolumab 410 389 359 337 305 275 213 139 73 29 3 Everolimus 411 366 324 287 265 241 187 115 61 20 2 Motzer et al. N Engl J Med. 2015;373(19):

Duration of Response (DOR) in Patients With mRCC
Majority of patients showed a response at first assessment 16 32 64 48 80 Time (Weeks) 96 112 128 Responders Ongoing response First response Off treatment Nivolumab Everolimus On treatment Motzer et al. N Engl J Med. 2015;373(19):

Landmark Overall Survival Analysis in Patients Treated and Not Treated Beyond Progression
In a landmark analysis beginning from 4 weeks post-progression, median OS was months (95% CI, 17.3–NE) in patients treated with nivolumab beyond progression and 11.4 months (95% CI, 9.4–14.6) in patients not treated beyond progression Median OS, months (95% CI) Treated beyond progression 28.1 (23.2–NE) Not treated beyond progression 15.0 (12.1–18.2) HR (95% CI), 0.41 (0.29–0.57) Overall survival with nivolumab 1.0 0.9 0.8 0.7 Treated beyond progression 0.6 Overall Survival (Probability) 0.5 0.4 0.3 Not treated beyond progression 0.2 0.1 0.0 3 6 9 12 15 18 21 24 27 30 33 Months Number of patients at risk TBP 153 153 146 142 132 123 96 65 30 17 2 NTBP 145 131 113 101 84 69 54 29 16 3 Escudier B et al. Poster presentation at ASCO

¿En primera línea y en combinación es superior que el actual standard de cuidado?

RJ Motzer et al. N Engl J Med 2018;378:1277-1290.
Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor-Risk Patients. Figure 1. Overall Survival and Progression-free Survival among IMDC Intermediate- and Poor-Risk Patients. Progression was defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1. For progression-free survival, the between-group difference did not meet the prespecified threshold (P=0.009) for statistical significance. IMDC denotes International Metastatic Renal Cell Carcinoma Database Consortium, NE not estimable, and NR not reached. RJ Motzer et al. N Engl J Med 2018;378:

¿Qué pasa si combinamos con antiangiogénicos?

¿Cuál es el rol en adyuvancia y neoadyuvancia?

Decision Point…. Immunotherapy PD-1/CTLA-4 Combination PD-1 alone

Time to Response and Durability of Response in Patients Who Discontinued Due to Adverse Events (Pooled Analysis of Checkmate 067 and 069 Schadendorf 2017: p4/Fig 2 Patients On treatment Off treatment First response Ongoing response 8 16 24 32 40 48 56 64 72 80 88 96 104 112 Weeks Minimum 18-month follow-up, median 21.3-month follow-up. Adapted from Schadendorf D et al. J Clin Oncol. 2017;35:

Adjuvant Therapy With Nivolumab Versus Ipilimumab After Complete Resection of Stage III/IV Melanoma: Updated Results from a Phase 3 Trial (CheckMate 238) Jeffrey Weber,1 Mario Mandala,2 Michele Del Vecchio,3 Helen Gogas,4 Ana M. Arance,5 C. Lance Cowey,6 Stéphane Dalle,7 Michael Schenker,8 Vanna Chiarion-Sileni,9 Ivan Marquez-Rodas,10 Jean-Jacques Grob,11 Marcus Butler,12 Mark R. Middleton,13 Michele Maio,14 Victoria Atkinson,15 Reinhard Dummer,16 Veerle de Pril,17 Anila Qureshi,17 Abdel Saci,17 James Larkin,18* Paolo A. Ascierto19* 1NYU Perlmutter Cancer Center, New York, New York, USA; 2Papa Giovanni XIII Hospital, Bergamo, Italy; 3Medical Oncology, National Cancer Institute, Milan, Italy; 4University of Athens, Athens, Greece; 5Hospital Clínic de Barcelona, Barcelona, Spain; 6Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, Texas, USA; 7Hospices Civils de Lyon, Pierre Bénite, France; 8Oncology Center Sf Nectarie Ltd., Craiova, Romania; 9Oncology Institute of Veneto IRCCS, Padua, Italy; 10General University Hospital Gregorio Marañón, Madrid, Spain; 11Hôpital de la Timone, Marseille, France; 12Princess Margaret Cancer Centre, Toronto, Ontario, Canada; 13Churchill Hospital, Oxford, United Kingdom; 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; 15Gallipoli Medical Research Foundation and University of Queensland, Brisbane, Australia; 16University Hospital Zurich, Switzerland; 17Bristol-Myers Squibb, Princeton, New Jersey, USA; 18Royal Marsden NHS Foundation Trust, London, UK; 19Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy; *Contributed equally to this study. Abstract Number 9502

Primary Endpoint: RFS in All Patients
NIVO IPI Events/patients 171/453 221/453 Median (95% CI) 30.8 (30.8, NR)a 24.1 (16.6, NR) HR (95% CI) 0.66 (0.54, 0.81) Log-rank P value <0.0001 RFS (%) Months 10 20 30 40 50 60 70 80 90 100 6 12 18 24 27 3 9 15 21 33 aMedian estimate not reliable or stable due to few patients at risk. 70% 66% 63% 60% 53% 50% NIVO IPI Number of patients at risk NIVO 453 353 311 280 205 28 394 331 291 264 7 314 251 216 149 23 363 270 230 204 5 IPI 42

Future Directions A new partner for PD-1 Overcoming Resistance
Less toxic than ipi More effective than PD-1 alone Overcoming Resistance Making ”cold” tumors “hot” Patient selection Role of biomarkers

Making Tumors “Hot” Responsive to Immunotherapy
Generate T-cells: + Combination CPIs + Immune activating antibodies or cytokines + TLR agonists or oncolytic viruses + IDO or macrophage inhibitors + Targeted therapies Bring T-cells into tumors: Vaccines TCR engineered ACT CAR engineered ACT

Frequency of genetic mutation1
Biomarkers Approximately 50% of melanomas contain mutations in the BRAF gene, a critical component of the growth promoting MAP kinase pathway1 Some melanomas have activating mutations in the human KIT, NRAS, and other genes1-3 Only BRAF is currently recommended to be tested in melanoma patients except in clinical trials BRAF is an activating mutation that is mutually exclusive with NRAS or c-KIT1 All of these activate the MAP-kinase pathway that promotes tumor growth1-3 Younger patients are more likely to have mutations5 Site of melanoma Frequency of genetic mutation1 BRAF GNA11 GNAQ KIT NRAS Acral surfaces 15% Mucosal surfaces 5% 20% Skin with chronic sun damage 10% 2% Skin without chronic sun damage 50% Uvea 55% 25% Biomarker-based stratification of patients is evolving in clinical trials. The NCCN expert panel supports obtaining tissue samples for genetic analysis4 Sources Sosman JA ASCO, 2011: Educational Book pages Curtin JA et al. J Clin Oncol. 2006;24: Van Raamsdonk CD et al. N Engl J Med. 2010;363: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma, v Hacker E et al. J Invest Dermatol 2010;130(1):

But despite these advances, unmet needs remain
NSCLC EGFR ALK ROS1 BRAF No actionable driver mutation How can we improve outcomes for the majority of NSCLC patients who have no actionable driver mutation?

Examples of Prognostic Implications of Immune Response
Correlation with Positive Outcome: Presence of TILs Associated with Increased Recurrence-Free Survival1 Correlation with Negative Outcome: Higher NSCLC-Infiltrating Tregs Associated with Worse Recurrence-Free Survival2 Recurrence-Free Survival (%) 1.0 0.8 0.6 0.4 0.2 0.0 10 20 30 40 50 60 Survival Time (Months) TIL– TIL+ P=0.011 Recurrence-Free Survival (%) Survival Time (Months) 24 36 12 48 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 FoxP3+ cell <3 FoxP3+ cell ≥3 Patients with Stage Ia NSCLC with Surgical Resection (N=273)1 Patients with Stage I–III NSCLC with Surgical Resection (N=100)2 FoxP3 cell < (≥) 3 = lower (higher) levels of FoxP3; TILs = tumor-infiltrating lymphocytes; Tregs = regulatory T cells. 1. Shimizu K, et al. J Thorac Oncol. 2010;5: Horne ZD, et al. J Surg Res. 2011;171:1-5.

Respuestas a terapias Anti PD-1/PD-L1:
Papel de la Histología, expresión de PDL-1 y estado mutacional Para los 3 anticuerpos disponibles actualmente: La expresión de PD-L1 está fuertemente asociada con mejores tasas de respuesta. Las respuestas ocurren independientemente de la histología, antecedente de tabaquismo y estado mutacional (EGFR/K-ras).

Tumor Mutational Burden (TMB)
Tumors with more mutations are more likely to respond to immunotherapies, because of the increased likelihood that they will have neoantigens that can be targeted by the immune system. TMB is a measurement of the total number of coding somatic base substitution and indel mutations occurring in a tumor specimen, per megabase of coding genome assessed. TMB is measured by algorithm and this approach is being clinically validated, currently available on OP’s request as research use only.

TMB IS A BIOMARKER FOR RESPONSE TO IMMUNOTHERAPY
Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Rizvi et al., Science, 2015 Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma Snyder et al., NEJM, 2014

Conclusiones La caracterización molecular del Cáncer nos ha mostrado realmente la muy compleja heterogeneidad de esta enfermedad y gracias a esto hemos entendido las fallas anteriores en decisiones terapéuticas. Muy probablemente, los estudios clínicos que hemos realizado ya no tendrán, dentro de poco, una gran validez científica pues hay que entender que “one size fits all” no aplica en esta enfermedad. Es solo a través del conocimiento de las mutaciones genéticas específicas y el desarrollo de terapias dirigidas a ellas que lograremos cambiar la historia natural de la enfermedad.

Mensajes El cáncer es una enfermedad causada por alteraciones genéticas generalmente múltiples, heterogéneas, intercambiables. La detección de quien conduce la enfermedad al inicio y en cada momento de la misma seria determinante para conducir el tratamiento y a veces corregir el rumbo. Las plataformas genómicas pueden detectar alteraciones potencialmente blanco de tratamientos específicos. Los futuros estudios deberían incluir con mas frecuencia estas determinaciones. La accesibilidad y su validación en más estudios clínicos permitiría seleccionar pacientes que podrían beneficiarse de tratamientos específicos así como determinar quienes no tendrían beneficios de tratamientos establecidos.

Combinatorial immunotherapy
Chemotherapy Radiotherapy anti-CD137 Vaccination IDO inh anti-OX40 anti-CTLA4 anti-PD1 anti-PDL1 Adoptive T-cell immunotherapy anti-CD40 Anti-angiogenic therapy Clinical standard Clinical trials Preclinical studies Treg depletion/ inactivation Perez Gracia, et al. Curr Opinion Immunol 2014

What Is Being Tested in the Immune Checkpoint Inhibitor Perioperative trials?<br />
Presented By Naomi Haas at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Presented By Naomi Haas at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

The future of Immuno Oncology in RCC (4)
Presented By Bernard Escudier at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Feces composition differs between responders and non responders to IO

Feces modification by antibiotics may negatively impact efficacy of IO

The future of Immuno Oncology in RCC (4)

PROBLEMAS IMPORTANTES
Necesitamos comprender los mecanismos de resistencia y desarrollar nuevas estrategias para sortearlos. Los pacientes que responden son importantes pero preocupan los que no responden. Necesitamos mejores biomarcadores para seleccionar los pacientes que se beneficiaran. La toxicidad es manejable salvo la toxicidad financiera que es de grado ¾ con alto riesgo de transformarse en grado 5 matando al sistema y limitando el acceso de los pacientes a los nuevos tratamientos.

Presented By Ravi Madan at 2014 ASCO Annual Meeting
Slide 19 Presented By Ravi Madan at 2014 ASCO Annual Meeting

Presented By Ravi Madan at 2014 ASCO Annual Meeting
Slide 28 Presented By Ravi Madan at 2014 ASCO Annual Meeting

Conclusiones La inmunoterapia puede enlentecer el crecimiento de los tumores más que alterar su progresión a corto término. La inmunoterapia puede ejercer su efecto por un largo periodo de tiempo. Combinaciones terapéuticas diseñadas racionalmente pueden lograr efectos sinérgicos de alto impacto. Hoy logramos contener la evolución de muchos tipos de tumores Tal vez estemos curando algunos.

Muchas Gracias Dr. Carlos Silva
Hospital Británico de Buenos Aires-Hospital Universitario Austral Universidad Católica Argentina

INMUNO-ONCOLOGIA Estado actual y futuro Cáncer Renal, Melanoma, Cáncer de Pulmón y Medicina de Precisión Dr. Carlos Silva Hospital Británico de Buenos.

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