Immunotherapy and CancerMauricio Burotto MD

National Cancer Institute

National Institutes of Health

DISCLOSURE

• Nothing to disclose

Nature 2001

Nature 2008

Applied Biosystems 3730xl

Illumina (Solexa) sequencing

Ion Proton Machine

OMICS

GENOMICS

TRANSCIPTOMICS

PROTEOMICS

METABOLOMICS

IMMUNOMICS

MICROBIOMICS

EPIGENOMICS

The Hot topic…

Genomics Deep sequencing

Stem Cells

Cancer Metabolism

EpigenomicsInmunotherapy

Clonal evoution

Target Therapy

Cancer ImmunotherapyType Specific Tumor Stage FDA

Interleuquines IL-2IL-15

Melanoma IV yesNo

Vaccines Sipileucel-TProsvac

Prostate IV yesNo

Check point inhibitors

Anti-CTLA4Anti-PD1Anti-PDL1

MelanomaNSCLC

IV yesyesyes

Adoptive Cell Therapy

CARsTILs

ALL NHL IV No

Target therapy in Cancer

• Bevacizumab Antiangiogenic therapy

• FDA approved for – RCC– NSCLC– CRC– Ovarian Cancer– Cervical Cancer– Gliobastoma

The ”Real’” Target therapy

• Cancer therapy pardigm in 2000

• CML Philadelphia cromosome 9/22

• NSCLC and history of EGFR

• Melanoma and the BRAF

Science 2002

Evolucion clonal

Heterogeneidad molecular

Gerlinger NEJM 2012

Immune system

• Innate immune system– Neutrophiles– Complement – NK

• Adaptive immune system– B cell– T cell– Antibodies

Immune system

• Innate immune system– Neutrophiles– Complement – NK

• Adaptive immune system– B cell

– T cell– Antibodies

Therapeutic Cancer Vaccines

• Designed to generate a targeted anti-tumor immune response

• Associated with minimal toxicities

• May have delayed effects relative to standard cytotoxic chemotherapy

• May have an impact beyond the period of administration

Slide 4

Sipuleucel-T: Activates Immune Cells Ex Vivo

Prostvac: Off the Shelf Vaccine

Phase II Trial: Prostvac <br />Extended Overall Survival in mCRPC

Presented By Ravi Madan at 2014 ASCO Annual Meeting

Immune Checkpoint Inhibitors

• Checkpoint molecules are the immune system ‘s way to auto-regulate

• Blocking these molecules can enhance T-cell activity

• Immune Checkpoint Targets– CTLA-4 (activated T cells)

– PD-1 (activated T and B cells)

– PDL-1 ( can be expressed on tumor cells)

CTLA-4 Checkpoint Inhibition

CTLA-4 Checkpoint Inhibition

Slide 14

Slide 35

Impressive Activity for Anti-PD-1 in RCC

• 57-year-old patient had developed progressive disease after receiving sunitinib, temsirolimus, sorafenib, and pazopanib

• Rx with Nivolumab (anti-PD-1) at 1 mg/kg q 2 wks x 2 years

• Completed 12 cycles – now with PET Complete Response

Pretreatment 6 months

Anti-PD-1 (MK-3475): <br />example of a clinical responses

Immunotherapies combination

Cellular therapies

• TMO– Allogeneic – DLI

• T Cell adoptive therapy

– TILs– CARS ( Chimeric antigen receptor)

Adoptive cell transfer immunotherapy

CARs

Perspective on how treatments in cancer are built

Industry

FDA EMA

NCCNASCO ESMO CCO

Academiccenters NCI

More than 90% of cancer drugs approved since 2004 cost more than $20000 for 12 weeks of treatment.

Latin America and the Caribbean

•By 2020, it is estimated that more than 100 million people older than 60 years will be living in S.A

•1.7 million new cases of cancer will be diagnosed by 2020

•6% of the Latin American population is covered by national cancer registries, by contrast with 96% in the USA and 32% in Europe

•In three years, up to 65% of FDA-regulated clinical trials will be conducted outside the U.S.

Incidence of cancer is lower in Latin America 163 per 100 000 (rate) than in Europe 264 or the USA 300

Cancer mortality-to-incidenceratio for Latin America is 0.59, compared with 0.43 for the Europe and 0.35 in the USA [HIGH LETHALITY]

Ferlay et al , GLOBOCAN 2008http://globocan.iarc.fr (2012)

But

Goss et al. Lancet Oncol. 2013 ;14:391

Challenges to Conducting Clinical Trials in Latin America

• Longer regulatory activities– Regulatory authorization and ethics committee approval– Different local requirements between countries

• Lack of infrastructure – The need for electronic data collection systems.– Better training for the research team (radiologist, pathologist, nurses

etc.)

Outlook 2008. Tufts Center for the Study of Drug Development

Potential advantages to Conducting Clinical Trials in Latin America

• Patient enrollment– Shorter enrollment time

– Fewer or non competing studies in the region

– Most patients are treatment and trial naïve

– Up to 80% of the population is concentrated in big cities.

• Latin America is one of the most diverse regions in the world– Diversity in ethnicity

– However there are regions with very homogenous population (indigenous)

– Example: Chile has the highest incidence of gastric and gallbladder cancer in the world

Outlook 2008. Tufts Center for the Study of Drug Development

Cancer Research in Latin America and the Caribbean

Accrual opportunities

Novel designs and concepts

Pharmacogenomics studies

Tito FojoMaureen Edgerly

Giuseppe GiacconeArun Rajan

Wilfred SteinKrastan BlagoevJohn Marshall

Eva SzaboMaureen Edgerly

James GulleyRobert Motzer

Agradecimientos

Clinical Research Center Staff