1. Renal Cancer Immunotherapy Walter Stadler

2. 2 Renal cancer natural history

3. Manola J et al. Clin Cancer Res 2011;17:5443-5450 International prognostic model βSE Square root of days from diagnosis to study entry −0.01920.002 ECOG performance status 0−1.5240.11 ECOG performance status 1−0.8380.11 Number of metastatic sites0.3240.032 Protocol immunotherapy−0.5740.094 Natural log of hemoglobin−2.470.20 Natural log of LDH0.6110.062 Square root of white blood count 0.6230.071 1/Square root of alkaline phosphatase −6.6651.39 Serum calcium0.1050.033

4. Treatment: HD IL2 Cytokine Working Group trial HD IL2 vs sc IL2/IFNA –HD IL2: 600,000 IU/kg q8 o x 14 doses –sc IL2/IFNA: 5 x 10 6 IU/m 2 4d/wk IL2; 5 x10 6 IU/m 2 2d/wk Selection criteria –Non-clear cell have minimal to no benefit –Suggestion that post-VEGFR TKI treatment has higher toxicity and lower efficacy sc IL2/IFNAHD IL2 Pt number9195 Deaths11 CR38 (p= 0.21) PR614 Resp. Duration15 mo24 mo (p=0.18) Med. Surv.13 mo17 mo (p = 0.21) Durable 3 yr CR07 (p=0.01)

5. Nivolumab (anti-PD1) in renal cancer Population Dose (mg/kg) Patients (n) ORR n (%) Duration of Response (mo) SD  24 wk n (%) PFSR at 24 wk (%) ALL RCC1, 10339 (27)5.6+ to 22.3+9 (27)56 RCC 1174 (24) 5.6+ to17.5+ 4 (24)47 10165 (31)* 8.4 to 22.3+ 5 (31)67 *One CR. Phase 3 vs everolimus in progress Multiple PD1 pathway inhibitor trials in progress

6. 6 MPDL3280A Phase 1a (anti-PDL1) RECIST 1.1 Response Rate (ORR) SD of 24 Weeks or Longer 24-Week PFS Overall population (N = 140) 21%16%45% RCC* (n = 47) 13%32%53% Clear cell (n = 40) 13% 35%57% Non-clear cell (n = 6) 17% 020% * 1 patient with unknown histology. Includes sarcomatoid and papillary RCC. All patients first dosed prior to August 1, 2012; data cutoff February 1, 2013. ORR includes unconfirmed PR/CR and confirmed PR/CR. Cho, et al, ASCO 2013

7. 7Renal Cancer| Peptide vaccine IMA901 multi-peptide –10 different tumor-associated –Not normal tissue –In-vitro immunogenic –HLA-A*02 restricted –Pharmaceutical grade Metastatic disease HLA-A*02 positive No prior therapy N = 330 Sunitinib IMA901 + GM-CSF 1 st cycle with cyclophosphamide Overall Survival

8. 8Renal Cancer| Dendritic Cell Therapy: AGS-003 RNA isolated from tumor cells Loaded on dendritic cells isolated through leukapheresis Administered intradermal Metastatic disease No prior therapy Cytoreductive nephrectomy N = 450 Sunitinib + AGS-003 Overall Survival

9. 9Renal Cancer| RCC Immunotherapy Conclusions Has always been considered an “immunotherapy responsive tumor HD-IL2 leads to rare sustained complete responses PD1 pathway inhibitors are promising Other immunotherapies are being investigated