Jordi RodonVall d’Hebron Institute of Oncology

(VHIO)Vall d’Hebron University Hospital

Barcelona

Immunotherapy in glioblastoma

Immunotherapy in glioblastoma

Blood-Brain-BarrierTumor burden

Immunosuppressive treatmentsSearch for better, specific molecular

targetsBetter understand side-effects

Heterogeneity in GBM

Sturm et al. Nature Rev. Cancer 2015

Johnson et al. Science 2014

Sturm, Witt, Hovestadt, Khuong-Quang et al., Cancer Cell

Somatic mutations in cancer

Clinical trials for glioma using immunotherapy

Calinescu, Immunotherapy 2015.Slide provided by E. Pineda

• Peptide vaccination• EGFRVIII • IDH1 • Multipeptide

• Dendritic cell-based therapy

• Adoptive cell therapy (CAR)

• Immunocheckpoint inhibitors (PD1/PD-L1)

• Tumor targeting antibodies (EGFR)

• Immunovirotherapy

• Inhibitors of immunosuppressive pathways

– IDO inhibitors, – TGFb inhibitors

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• Peptide vaccination• EGFRVIII • IDH1 • Multipeptide

• Dendritic cell-based therapy

• Adoptive cell therapy (CAR)

• Immunocheckpoint inhibitors (PD1/PD-L1)

• Tumor targeting antibodies (EGFR)

• Immunovirotherapy

• Inhibitors of immunosuppressive pathways

– IDO inhibitors, – TGFb inhibitors

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Immune Checkpoint inhibitors

Curry, Neuro-Oncology 2015.

Preusser, Nat rev neurology 2015.

Immune check-point inhibitors in preclinical glioma models

Wainwright, CCR 2015

Clinical activity and safety of atezolizumab (anti PDL1) in patients with glioblastoma

(GBM)

Rimas V. Lukas et al. SNO 2015.

Checkmate 143 – Phase 2-3

RDT and Immune checkpoint inhibitors in preclinical glioma models

Zeng, IJROBP 2013. Belcaid, PlosOne 2014.

“Respecto al estudio MK3475-499 (Pembrolizumab en combinación con radiación en pacientes con GBM avanzado), cuya visita de validación tuvo lugar el pasado mes de Julio, lamento informarle que finalmente España no va a participar en el estudio, debido a la dificultad del esquema que presentaba en el estudio con la re-irradiación”

Combos with PD-1/PDL-1 as the backbone

Anderson AC, et al. Immunity 2016.

Melero I et al. Nat Rev Cancer 2015.

FACTS•Effect on immune function, cell proliferation-differenciation, cell adhesion, extracellular matrix production, cell motility, angiogenesis, and cytokine production•Aberrant TGF-β signaling is present in most malignancies, such as glioblastoma, hepatocellular carcinoma, pancreatic cancer, and myelodysplastic syndromes.

•Targeting TGF-b may:• Inhibit tumor growth by decreasing cell

signaling• Stimulate anti-tumor immunogenicity• Decrease angiogenesis.• Inhibit Cancer Stem Cells

TGFβ pathway and relevance in cancer

TGFβ pathway pharmacology

Selectivity pk Issues Notes

Monoclonal antibodies

GC1008human IgG4 MAb

(Genzyme/Genentech)

Phase ITGFb 1, 2

and 3

•Potentially no

interactions•IV

BBB (?)

Initially developed for

Idiopathic Pulmonary

Fibrosis

Small molecules

LY2157299(Lilly)

Phase I (GBM)TGFb

receptor I and II

•Interactions are probable

•Orally

Cardiovascular toxicity

Antisense oligonucleotide

s

AP 12009(Antisense Pharma)

Phase III (intratumora)

and phase I (iv)TGFb-2

•Potentially no

interactions•Short half

live

•Requires prolongued iv infusions or intratumoral

delivery•Intratumoral concentration

s when delivered iv

(?)

Other antisense

oligos (Genasense and YM155)

Small Peptides NAFB001(Digna Biotech)

Phase II (scleroderma)

TGFb-1 NA TopicalEscleroderma y actinic fibrosis,

skin cancer.

TGFβ pathway and challenges for drug development (I)

Premalignant and malignant skin lesions (keratoacanthoma, SCC, BCC), seen after several doses of GC1008 (Fresolimumab, a monoclonal antibody).Lesions improved when treatment was discontinued.

Morris JC, PLOSOne 2014

Loss-of-function in the TGF-b signaling pathway is observed in patients with Loeys-Dietz Syndrome (LDS), a subset of Marfan Syndrome.

Normal aorta wall (elastin)

Aorta wall from LDS pt (elastin)

ID1 expression pre and post LY2157299 treatment for a  24-year-old patient.

Anido et al. (2010)  

pSMAD Inhibition in PBMCs (160mg/day)

First-in-Human Dose (FHD) Study of the Oral TGF-β Receptor I Kinase Inhibitor LY2157299 in Patients with Treatment-Refractory Malignant Glioma

Minor architectural alteration of the elastic fibers with mild mucynosis (Alcian Blue). We can conclude that this findings had no clinical relevance.

Radiographic responses in glioma patients based on Macdonald criteria

Radiographic Response Over Time: ➢ The clinical responders had an initial

disease stabilization followed by radiographic tumor lesion reduction

Rodon et al. CCR, 2014

First-in-Human Dose (FHD) Study of the Oral TGF-β Receptor I Kinase Inhibitor LY2157299 in Patients with Treatment-Refractory Malignant Glioma

But…

#ACTR-16Phase 2 study evaluating safety, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of the oral transforming growth factor-beta (TGF-β) receptor I kinase inhibitor galunisertib when combined with chemoradiotherapy in newly diagnosed malignant gliomas

1Annick Desjardins, 2Cristina Suarez, 3Peter Forsyth, 4Ivelina Gueorguieva, 4Ann Cleverly, 5Michael Man, 5Tiana Burkholder, 5Durisala Desaiah, 5Michael M Lahn, 5Susan C Guba 6Wolfgang Wick, 2Jordi Rodon

1The Preston Robert Tisch Brain Tumor Center at Duke, Duke University, Durham, NC, USA; 1Medical Oncology, Vall d’Hebron, Barcelona, Spain; 3H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 4Eli Lilly and Company, Erl Wood, UK; 5Eli Lilly and Company, Indianapolis, IN, USA; 6The University of Heidelberg, Heidelberg, Germany

Phase 2 Study Design

Galunisertib

• Patients were randomized in a 3:1 ratio

• Galunisertib+TMZ+RTX, (N = 40)

• TMZ+RTX (N = 16)

The primary objective of this phase 2 study was to confirm the tolerability and evaluate the pharmacodynamic effect of galunisertib in combination with standard radiochemotherapy treatment in patients with newly diagnosed glioblastoma (GB) (as measured by changes in response biomarkers and their relationship to clinical benefit [for example, Tregs [CD4+CD25+CD127-/LOFOX P3+] and correlation with overall survival)

Overall Survival

26

Progression-Free Survival

27

Post-treatment (Cycle 5) Delta Tregs Impact on OS

28

• Higher delta (change from baseline) in post-treatment (cycle 4 and 5) Tregs [CD4+CD25+CD127-/LOFOX P3+] were associated with longer survival (not statistically significant when adjusting for multiplicity). See plot for post-treatment Tregs changes at cycle 5 to illustrate the trend observed

• A similar pattern was observed in ratios normalized by CD4+ or CD8+

Vaccines

29

Rindopepimut (CDX-110)

Lowenstein ASCO 2014

Vaccine designed to generate a specific immune response against EGFRvIII-expressing tumors

– Consists of the EGFRvIII antigen (unique 13 amino acid peptide sequence) chemically conjugated to Keyhole Limpet Hemocyanin with 150ug of GM-CSF as an Adjuvant

– “Off the shelf” vaccine recognized across HLA types

Phase II trials Rindopepimut

Lai et al. SNO 2011. Sampson, JCO 2010

ACT IV: phase III trial of Rindopepimut in 1L GBM

Weller, ESMO 2015

✓ November 2011: Start Date✓ 30 September 2014: The vaccine’s manufacturer, Celldex Therapeutics, informed that they have completed enrollment. ✓ March 7, 2016, Celldex announced that it was halting this phase III trial. The decision was based on findings from an interim data analysis which showed that patients receiving rindopepimut were unlikely to have an improvement in overall survival compared with patients in the control arm.

ReACT – Recurrent GBM ReACT: Long-term survival from a randomized phase II study of

rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma

Reardon, ASCO 2015

Other vaccines

•Neoepitope vaccines • Rindopepimut (EGFRvIII)• IDH1 (IDH1R132H)> NOA-16-Trial

• Multipeptide vaccines • ICT-107• SL-701• IMA-950 (11 peptides)

•Dendritic cell vaccines• ICT-107 (6 Antigens)• DCVax-L (tumor lysate)• CMV (pp65 CMV)

•Individualized approaches?

Gao J, Trends in Immunotherapy, 2013

CARTs (Chimeric Antigen Receptor T-cells)

Ahmed et al. HER2-CAR CMV T in Glioblastoma

HER2

CMV

• 16 patients received CARTs• Well tolerated • HER2-CAR CMV T cells were transiently

seen in peripheral blood• 1 PR and 4 prolonged SD

Safe therapy (no cytokine-release syndrome) Robust cytotoxic response

Can clinical efficacy improve with conditioning chemotherapy and/or delivery systems?

Combos?

Razavi SM, Lee KE, Jin BE, Aujla PS, Gholamin S and Li G (2016) Immune Evasion Strategies of Glioblastoma. Front. Surg. 3:11.

Check-point inhibitors (PDL1)

Vaccines

CART cells orEngineered T cells (TCRs)

Immunomodulators (inh TGFbeta, IL10)

Reduce Tregs (GITR, CTLA4, TMZ, CTX,)

Adjuvants

Dendritic cell-based therapy

Tumor targeting antibodies (EGFR)

Immunovirotherapy

Radiation (abscopal effect)

Temozolamide, steroids