Role of Immunotherapy in the Era of Targeted Therapies

1
Role of Immunotherapy in the Era of Targeted
Therapies

• Immunotherapy is the only established cure for
  patients with stage 4 kidney cancer
• Many More patients will be helped with targeted
  therapies than Immunotherapy
• Little experience or data on combining
  immunotherapy with targeted therapy

2
Interleukin-2 Therapy for Kidney Cancer

• FDA-approved 1992 for Kidney Cancer
• First Approved Immunotherapy for any advanced
  human cancer
• Durable Complete Remissions
• High Toxicity
• Low Response Rates
• Low Dose regimens inferior
• Limited Physician acceptance and experience
• Interleukin-2, IL-2, aldesleukin, Proleukin the
  same

3
Role of IL-2 in the Immune Response
Roitt I, et al. Immunology. 1996811.
4
Interleukin-2 Biololgical Effects

• Proliferation of Lymphocytes in test tube and
  in the patient
• Activation of T-lymphocytes Natural Killer
  Cells Lymphokine-Activated Killer Cells
• Trafficing of Lymphocytes Cells move into
  tissues
• Production of Cytokines gamma-interferon tu
  mor necrosis factor

5
High-Dose IV Bolus rIL-2 in Metastatic RCC
Course of Treatment
5 to 9 days
5 days
5 days
Cycle 1
Cycle 2

• Median number of doses per course 7 per first
  treatment cycle

Note Dosages above 600,000 IU/kg/dose are not
currently listed in the approved labeling for
aldesleukin for injection. Fyfe G, et al. J Clin
Oncol. 199513688-696. Kammula US, et al.
Cancer. 199883797.
6
Toxicity of Interleukin-2 Therapy

• Fever,Chills, Rash 100
• Hypotension 78
• Severe decrease kidney function 38
• Jaundice 18
• Respiratory Distress 15
• Coma 6
• Nausea and Vomiting 50
• Death 1-2
• Only healthy patients can withstand therapy
• Rarely recommended over age 60

7
High-dose IL-2 at California Pacific
5 of 50 patients in 10 years
8
IL-2 Response Duration All Responding Patients
Kaplan-Meier Estimate
1.0
0.8
0.6
Probability of survival
Probability of continuing response
0.4
0.2
0.0
70
80
0
10
20
30
40
50
60
90
100
110
120
130
140
Duration of survival (mo)
Fisher R, et al. Cancer J Sci Amer. 20006(suppl
1)S55-S57.
9
Interleukin 2 Patient Selection

• Age lt50
• Physically feels well
• Clear Cell Histology
• Metastases limited to lungs or bones only
• No other medical problems
• Tumor positive of CA IX

10
IFN-? in Renal Cell Carcinoma

• Immunostimulant, weaker but less toxic than IL-2
• Well Tolerated
• Fatigue, loss of appetite, nausea, flu-symptoms
• Survival inferior to sunitinib or temsirolimus
• 6-15 response rate, rarely complete responses
• Potential use in combination therapy with IL-2 or
  targeted therapy

11
Experimental Immunotherapy

• Ipilimumab- Anti-Cytotoxic T-Lymphocyte Antigen 4
  (CTLA-4) monoclonal antibody removes the brake
  on T-cells autoimmune effects 6
  responses in 40 patients in phase 1
• TRIST -Trovax Renal Immunotherapy Survival Trial
• phase III trial of Trovax vaccine with
  sunitinib for stage IV kidney cancer
• Autologous Dendritic cell vacccine
• Allogeneic Stem Cell Transplant

12
Immunotherapy Targeted Therapy Combinations

• Interferon with bevacizumab trial promising
• Interferon with sunitinib or temsirolimus
  trials--no benefit
• Inteleukin-2 with bevacizumab small trial begun
• Interleukin-2 with sorafenib trial begin
• Sorafenib with interferon trials begun
• Sunitinib with Trovax vaccine trial
  begun Sunitinib alone vs sunitinib with Trovax