The immunotherapy of cancer: past, present & the next frontier Ira Mellman Genentech South San Francisco, California
William Coley and the birth of cancer immunotherapy Elie Metchnikoff & Paul Ehrlich won the Nobel Prize 3 months later
Past activities focused on vaccines & cytokines Discovery that T cells in cancer patients detected tumor-associated epitopes (Thierry Boon, Brussels) Attempts to boost T cell responses with (peptide) vaccines o Thousands treated, few clinical responses o Poor mechanistic understanding of immunization Attempts to boost T cell responses with cytokines (IL-2, interferon) o Promising but limited clinical activity in various settings o On target toxicity an additional limit to broad use o Limited mechanistic understanding Cancer immunology & immunotherapy fails to find a home in either immunology or cancer biology
Dawn of the present: Ipilumumab (anti-CTLA4) elicits low frequency but durable responses in metastatic melanoma Ipi Ipi+gp100 gp100 alone Hodi et al (2010) NEJM
The sun continues to rise: anti-PD-1 is superior to and better tolerated than anti-CTLA4 (melanoma) Robert C et al. N Engl J Med 2015;372:2521-2532.
What we have learned: immunosuppression is a rate limiting step to effective anti-tumor immunity* *for some patients Anti-CTLA4 ipilimumab tremilimumab Immuno- suppression vaccines Anti-PD-L1/PD-1 nivolumab pembrolizumab atezolizumab durvalumab Chen & Mellman (2013) Immunity
Blocking the PD-L1/PD-1 axis restores, or prevents loss of, T cell activity • PD-L1/PD-1 interaction inhibits T cell activation, attenuates or tumor- infiltrating effector function, maintains immune cells IFN g -mediated up-regulation of immune homeostasis tumor PD-L1 PD-L1/PD-1 inhibits • Tumors & surrounding cells up- tumor cell killing regulate PD-L1 in response to T Shp-2 cell activity MAPK PI3K pathways • Blocking PD-L1/PD-1 restores or prevents loss of T effector function
a PD-L1 and a PD-1 exhibit similar early activities despite blocking different secondary interactions a PD-L1 blocks PD-L1 interaction with inhibitory B7.1 on T cells PD-L2 or a PD-1 blocks interaction with both PD-L1 & -L2 on myeloid cells
Broad activity for anti-PD-L1/PD-1 in human cancer Head & neck cancer Glioblastoma Lung cancer Breast cancer Pancreatic Liver cancer Gastric Melanoma Ovarian Renal cancer Hodgkin lymphoma Colorectal cancer Bladder cancer Broad activity, but only subset of patients benefit: ~10-30%
Cancer Immunotherapy: present focus I Diagnostic biomarkers to enrich responders to PD-L1/PD-1 • Identify patients most likely to respond to a PD-L1/PD-1 ipilimumab� • Identify combinations that extend the depth and breadth of response to PD-L1/PD-1 • Investigate new targets to Anti-PD-L1/PD-1� overcome immunosuppression, nivolumab� pembrolizumab� enhance T cell expansion atezolizumab�
PD-L1 expression predicts clinical response: an imperfect but useful Dx biomarker Immune cells Tumor cells Tumor and immune cells (ICs) (TCs) (TCs and ICs) Predictive of benefit in Predictive of benefit in bladder cancer (ORR/OS) 1 lung cancer (ORR/PFS/OS) 2 WCLC 2015 1 IMvigor 210 (ECC 2015), 2 POPLAR (ECC 2015)
PD-L1 expression by tumors can enrich for responses to atezolizumab (anti-PD-L1) in NSCLC and bladder cancer Lung cancer (TC + IC) Bladder cancer (IC only) Survival hazard ratio* Overall survival* Subgroup� (%� of� enrolled� patients)� 100 TC3� or� IC3� (16%)� 0.49� � 80 TC2/3� or� IC2/3� (37%)� 0.54� Overall survival Median OS Not Reached (95% CI, 9.0-NE) 60 TC1/2/3� or� IC1/2/3� (68%)� 0.59� TC0� and� IC0� (32%)� 1.04� 40 IC2/3 20 Median OS 7.6 mo IC0/1 (95% CI, 4.7-NE) 0.73� � ITT� (N� =� 287)� + Censored 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 � 0.2� 1� 2� Time (months) � Ratio a � Hazard� In� favor� of� atezolizumab� In� favor� of� docetaxel� Rosenberg et al (2015) ECC Vansteenkiste et al (2015) ECC
PD-L2 also correlates with clinical benefit to atezoluzumab (n=238 patients) OS HR: 0.39 (95%CI: 0.22 – 0.69) OS HR: 0.46 (95%CI: 0.27 – 0.78) Atezolizumab (PD-L1 high) Atezolizumab (PD-L2 high) Atezolizumab (PD-L1 low) Atezolizumab (PD-L2 low) Docetaxel (PD-L2 high) Docetaxel (PD-L1 low) Docetaxel (PD-L2 low) Docetaxel (PD-L1 high) OS� HR� is� for� atezolizumab� vs� docetaxel.� OS� HR� is� for� atezolizumab� vs� docetaxel.� PD-L2� ‘ high ’ � defined� as� ≥ � median� expression;� PD-L2� ‘ low ’ � defined� as� <� median� expression.� � PD-L1� ‘ high ’ � defined� as� ≥ � median� expression;� PD-L1� ‘ low ’ � defined� as� <� median� expression.� � OS HR: 0.44 (95%CI: 0.26 – 0.77) OS HR: 0.43 (95%CI: 0.24 – 0.76) Atezolizumab (PD-1 high) Atezolizumab (B7.1 high) Atezolizumab (B7.1 low) Atezolizumab (PD-1 low) Docetaxel (B7.1 high) Docetaxel (PD-1 high) Docetaxel (PD-1 low) Docetaxel (B7.1 low) OS� HR� is� for� atezolizumab� vs� docetaxel.� OS� HR� is� for� atezolizumab� vs� docetaxel.� PD-1� ‘ high ’ � defined� as� ≥ � median� expression;� PD-1� ‘ low ’ � defined� as� <� median� expression.� � B7.1� ‘ high ’ � defined� as� ≥ � median� expression;� B7.1� ‘ low ’ � defined� as� <� median� expression.� � Schmid et al (2015) ECC; data from Fluidigm panel
The predictive power of PD- L1+ IC’s suggests a special role for infiltrating immune cells in anti-tumor T cell function * Taube et al (2012) Science Transl. Med. IFN g + T cell effectors • Why can PD-L1 expression by immune infiltrating cells more predictive than PD-L1+ tumor cells? • Do PD-L1+ myeloid cells, not tumor cells, regulate T cell function at baseline? • What is the actual mechanism of PD- 1-mediated suppression? Tumor
PD-1 acts by down-regulating T cell costimulation via CD28, not TCR signaling Dendritic cell/ macrophage MHCp B7.1/ PD-L1 B7.2 PD-1 CD28 TCR P T cell P P P Lck PI3K ZAP P P 70 P P Shp2 Tumor� • Infiltrating immune cells may provide costimulation to help activate TILs, and then homestatically turn them off • Importance of B7.1 and its interaction with PD-L1? Hui et al and Kamphorst et al (2016) Submitted
Cancer Immunotherapy: present focus II Combinations • Identify patients most likely to respond to a PD-L1/PD-1 ipilimumab� • Identify combinations that extend the depth and breadth of response to PD-L1/PD-1 • Investigate new targets to Anti-PD-L1/PD-1� overcome immunosuppression, nivolumab� pembrolizumab� enhance T cell expansion atezolizumab�
Combinations of immunotherapeutics or immunotherapeutics with SOC/targeted therapies Hypothetical OS Kaplan Meier curves Control Targeted/chemo therapy Immunotherapy Immunotherapy+ Targeted/chemo therapy • Agents must be safe in combination with anti-PD-L1 • Targeted/chemo therapy should not interfere with immune response or immunotherapeutic mechanism of action
Combinations may extend the benefit of anti-PDL1 Chemo and targeted therapies • MEK is not required for T cell killing • MEK inhibition slows T cell apoptosis in tumors
Chemotherapy as immunotherapy: effect of platins on preclinical efficacy and immunobiology 2000 Control Platinum chemo Tumor CD8+ (cell type) Tumor volume (mm 3 ) Anti-PDL1 1500 60 Anti-PDL1/ Platinum chemo 40 1000 20 500 0 0 Ctrl Plat 1 Plat 2 Plat 3 Taxane 1 Taxane 2 0 10 20 30 40 50 60 Day Tumor CD4 + FoxP3 + (cell type) Tumor CD11b + Ly6C + (cell type) 80 80 60 60 40 40 20 20 0 0 Ctrl Plat 1 Plat 2 Plat 3 Taxane 1 Taxane 2 Ctrl Plat 1 Plat 2 Plat 3 Taxane 1 Taxane 2 Camidge et al., 16 th World Conference on Lung Cancer, Sept 6-9, 2015 (Denver)
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