Cancer Immunotherapy and Precision Medicine Marianna Nuti Dipartimento

Cancer Immunotherapy and Precision Medicine Marianna Nuti Dipartimento di Medicina Sperimentale, UP Terapie Cellulari Policlinico Umberto I, marianna. nuti@uniroma 1. it Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010

August 19, 2010

Aggiornamenti sul tumore dell’ovaio Roma 16 dicembre 2010

CD 8 T cells Central memory CD 8 T cells Mlecnik et al. Jclin Oncol 2011; 29: 610

Dalla copertina di Science……. alla recente copertina del Time sull’impatto economico INCONTR AIOM 2016

Challenges for curing cancer today • It is not sufficient to “treat” the tumor • Treat the patient: individualized treatment • Immune system: unique repertoire of molecules and cells specialized to eliminate and control foreign material/sick cells/pathogens 6° MASTER in NEURO-ONCOLOGIA

Immunotherapy Targeted therapy Targets tumour Targets host Single agent immunotherapies cause slow-onset, durable responses Combination ? 6° MASTER in NEURO-ONCOLOGIA Single agent targeted therapies cause deep, rapid onset, but nondurable responses

The immune system • Unique repertoire of molecules and cells specialized to eliminate and control foreign material/sick cells/pathogens • Immune cells can “find” the target in all tissue discrict • Can be educated for recognition • Memory

IMMUNOTHERAPY: “universal” and “shared” therapies for different tumors • Immune system is active in all humans • All cancers can benefit from immunotherapy • The immune fitness of the patient is probably the best indicator of response to immunotherapy • Several factors contribute to immune fitness: microbiota, genetic factors, life style, neurological factors etc…

T cell the novel “drug”for treating cancer: T cells can clinically control cancer • First important evidence: T Lymphocytes can eliminate also large masses of tumor (1 Kg of tumor = 1012 cells) • Failure to achieve critical mass of T cells explains previous trials with disappointing results • Two potential solutions: - Infuse huge numbers of specific T cells - Activate small numbers of T cells in-situ (chemo/radio and target therapies) and expand them in large quantities (ICI)

T cell the novel “drug”for treating cancer: T cells can clinically control cancer • T cells can be “liberated” by immune-check point inhibitors • T cells can be adoptively transferred (car-T) • T cells can be induced in vivo by vaccination and/or chemo/radio therapies Palucka AK and Coussens LM, Cell 2016 6° MASTER in NEURO-ONCOLOGIA

New shapes of curves and new endpoints for clinical trials IDEAL KAPLANMEYER -Reduction in the risk of event is maintained proportional during the observation -Median Survival and HR are both good surrogate of treatment benfit TKIs KAPLAN-MEYER -Large benefit in favour of the experimental drug is captured entirely by the medians -No difference at the 12 -m landmark analysis is observed IMMUNO KAPLANMEYER -Medians do not capture the effect of the drug -Landmark analysis may be the best tool to magnify benefit that will be detected later in the study Pilotto S et al. Transl Lung Cancer Res

Future scenarios in immunotherapy treatment of cancer • Absolute need for combination of treatments • Novel “mentality” in designing treatment protocols and clinical trials • Patient personalized approach

Questions to be answered… Can immune biomarkers help? • Explain degree of heterogeneity in responses with ICI • How to extend ICI coverage to the majority of cancer patients who do not see control or regression of cancer (biomarkers of response and toxicity) • Should we start ICI treatment at diagnosis? Need of biomarkers of immune fitness (activation, suppression) • Should ICI treatment be continued beyond progression? Suspended? Otherapies to re-induce immunogenic death?

Biomarkers in immunotherapy: precision medicine in immunoncology • To identify early responders pts • To anticipate toxicity events • To monitor immunity during treatment • To stop immune therapy if ininfluent to response (not for resistance) • To tailor on the single pt the right schedule (precision immuno-oncology treatment)

Biomarcatori validati (più o meno…) • IMMUNOSCORE tissutale • Misura infiltrato immunitario, location infiltrato, può essere tipizzato grossolanamente: correla con prognosi • Possibile solitamente in partenza (tumore primario), non valuta dinamicità, manca di caratterizzazione specifica • MUTATIONAL LOAD • Per difetti riparo (MMRD) : ottima risposta con ICI • La valutazione non è in realtà utile ai fini clinici • IMMUNOMONITORING • Popolazioni cellulari periferiche indicative di attivazione e/o immunosuppression • Citochine-chemochine pro-anti-infiammatorie sieriche • Fondamentale personalizzazione e valutazione durante trattamento (per ora…) • BIOMARKERS NON IMMUNITY • LDH indice di high cell turnover e stress/hypoxia (LDH elevato correla con prognosi negativa) • Cell-free DNA, mi. RNA, exosomes

Immune related biomarkers: summary of findings related to response • T cells: q Increase in Absolute Lymphocyte count (ALC) , CD 4+ and CD 8+(Ki 67), low monocyte, low MDSC, high Treg (for IPI) q Pre existing primed CD 8+ T cells are maintained in long-term survivors (not naive converting to effectors…)…. reflects immunogenicity of tumor, capacity of that aplotype to present, rearrangements Tc. R q Association with low serum IL 15 (increased expression of TIM 3 and PD-1 on NK and T cells q High IL 4 and IFNgamma before IPI q High avidity T cell clones (example virus reactive , CMV), Less clonotype loss q ICOS upregulation after IPI, transcription factors EOMES and granzyme B + T cells Master di Immuno Oncologia 27 -29 Aprile 2017

Infiltrato infiammatorio NSCLC

B cells CD 8 T cells CD 4 T cells Confirmed by Djenidi et al. , J Immunol 2015 and Donnem et al. , Clin Cancer Res 2015

T cell the novel “drug”for treating cancer: evidences that T cells are involved also in determining the success of cancer therapies Therapeutic benefit from PD-1/PD-L 1 blockade requires “hindered” pre-existing immunity reinvigorated by the treatment

Il percorso per l’attivazione dei linfociti T anti tumore Presseur M. et al. , Nat Rev Neurology, 2015

Slide 13 Presented By Padmanee Sharma at 2016 ASCO Annual Meeting

Slide 22 Presented By Laura Chow at 2015 ASCO Annual Meeting

NEED TO EXPAND A SIGNIFICANT NUMBER OF SPECIFIC T CELLS Not all patients with an immunological response to pembro (anti-PD 1) have clinical benefit Huang, AC et al, Nature 2017

NEED TO EXPAND A SIGNIFICANT NUMBER OF SPECIFIC T CELLS 29 pts stage IV melanoma with prior anti-CTLA 4 treatment treated with PEMBRO • Most pts demonstrated immunological response ( CD 8 Tex cells Ki 67 pos) • Clinical failure due to: 1. Inability to induce immune reinvigoration 2. Imbalance between T cell reinvigoration and tumor burden • Magnitude of reinvigoration of circulationg Tex cells in relation to tumor burden correlates with clinical response Huang, AC et al, Nature 2017

ICI non responders/refractory pts are: • Pts with defects in IFN signaling • Pts with tolerogenic DC • Pts with defects in antigen presentation (beta-2 microglobulin) • Pts with unbalanced T-cell invigorating/tumour burden ratio ICI responders pts are: • Pts with high mutational load • Pts with defects in repair machinery • Pts with tumor-T cell inflammation

The cancer immunogram. Christian U. Blank et al. Science 2016; 352: 658 -660

T cell the novel “drug”for treating cancer: evidences that T cells are involved also in determining the success of cancer therapies CHEMOTHERAPY and TARGET THERAPY need an intact immune system to be efficacious

Designing Vaccines or re-invent chemo/target/radiotherapy protocols to increase specific anti tumor T cells trafficking to the tumor Nota bibliografica

Nivolumab OS: Prior sunitinib Nivolumab OS: Prior pazopanib Motzer RJ, ASCO 2016

Targeting dei recettori coinvolti nell’attivazione linfocitaria

CD 137 anti-TNF receptor 4 -1 BB: biomarker to identify naturally -occurring tumor reactive T cells in tumor • CD 137 is up regulated by TILs upon encounter with a tumor antigen • CD 137 in CD 8+ and CD 4+ T cells is MHC dependent • CD 137 expression identifies recently activated tumor specific T cells • Targeting del recettore con anticorpi agonisti in clinica: numerosi studi in fase 1, tossicità epatica • Targeting del recettore in studi di adoptive cell therapy per espansione T cells tumor specific

Added value of peripheral blood biomarkers: Take home message from initial immunomonitoring studies (…. real life) • Chance to monitor at different time points treatment induced changes • Peripheral blood biomarkers: a partial and dinamic picture strongly indicative of tumor immune scenario. Modifications of the repertoire /function of circulating immune cells is an early event ( earlier than tumor response) • Circulating cytokine and chemokine can anticipate the changes in target populations, can be alert of manifest immunesuppressive status, are indicators of activated recirculation and/or cross-talk of immune cells • All data should have a longitudinal setting per patient • We need to learn from our patients: …. longsurvivors, excellent responders, off-label etc… • Novel “mentality” in designing treatment protocols and clinical trials…Immunomonitoring guided trials

ALGORITHM of PATIENT SELECTION PARAMETERS FOR CANCER IMMUNOTHERAPY Botticelli , A. et al. 2017