1. Immunotherapy in Renal Cell Ca F.Ghadiri M.D Radiation Oncologist

2. Attempts to increase levels of immune lymphocytes capable of recognizing cancer antigens and destroying established cancers Immunotherapy

3. Evidence for Tumor Immunity Spontaneous regression: melanoma, lymphoma, RCC Regression of metastases after removal of primary tumor: pulmonary metastases from renal cell carcinoma Infiltration of tumors by lymphocytes and macrophages: melanoma and breast cancer Lymphocyte proliferation in draining lymph nodes Higher incidence of cancer after immunosuppression, immunodeficiency (AIDS, neonates), aging, etc.

4. Sponateous regressions First observed 60 years ago First observed 60 years ago Prospective assessment Prospective assessment 7% of patients 7% of patients Median duration of 2 years Median duration of 2 years Initial watchful waiting is appropriate Initial watchful waiting is appropriate Asymptomatic patients Asymptomatic patients Low volume disease Low volume disease Build this into clinical trial design Build this into clinical trial design

5. Tumor-specific Immune Response

6. Advanced RCC Treatment Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy Primary treatments are systemic therapy with molecularly targeted therapy or immunotherapy Surgery is palliative therapy Surgery is palliative therapy - Solitary metastatic site - Solitary recurrence following nephrectomy - Symptoms related to bulkiness of disease including pain, nausea, or GI obstruction

7. What have we got? Interferon-  Interferon-  Interleukin-2 Interleukin-2 Talactoferrin Sunitinib Sunitinib Sorafenib Sorafenib Pazopanib Pazopanib Bevacizumab +/- Ifn-  Bevacizumab +/- Ifn-  Temsirolimus Temsirolimus Everolimus Everolimus Axitinib Axitinib

9. Vaccines Yang JC & Childs R J Clin Oncol 2006; 24:5576

10. Interferon-  Introduced early 1980’s Introduced early 1980’s Response rate 15-20% Response rate 15-20% Complete remissions are rare (1-2%) Complete remissions are rare (1-2%) Reduces risk of death at 1 year by one third Reduces risk of death at 1 year by one third

11. Survival with interferon MSKCC scoring system 6 months > 3 risk factors: 144 pts (22%) 1 alive Risk Factors are: No prior nephrectomy KPS <80% Low Hb High corrected calcium High LDH 28 months 0 risk factors: 164 pts (25%) 30 alive (5%) 12 months 1 or 2 risk factors: 348 pts (53%) 23 alive (4%)

12. Interleukin-2 Protocols used High dose bolus (Rosenberg) High dose bolus (Rosenberg) High dose continuous infusion (West) High dose continuous infusion (West) Low dose bolus Low dose bolus Subcutaneous single agent Subcutaneous single agent SC combination (with IFN & 5-FU) (Atzpodien) SC combination (with IFN & 5-FU) (Atzpodien)

13. A meta-analysis of trials of Interleukin-2 in metastatic renal cell cancer Baaten, Voogd & Wagstaff Eur J Cancer 2004; 40:1127 Complete responses vs route of administration CIV=continuous infusion SC=subcutaneous injection BIV=intermettent bolus injection Duration of complete remissions

14. Immunotherapy Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-20% with median duration of 19-109 months Immunotherapy with IL-2 activates immune response against RCC resulting in tumor remission rates 10-20% with median duration of 19-109 months Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction Severe toxicity including hypotension, capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunction Treatment requires ICU monitoring Treatment requires ICU monitoring Used for patients that can tolerate side effects Used for patients that can tolerate side effects

15. Cytokine working party J. Clin. Oncol. 2003 Aug 15th HD IL-2 = 156 pts RR = 21% LD IL-2 = 150 pts RR = 13% p=0.04 vs HD SC IL-2 RR = 10% p=0.033 vs HD Survival of complete responders

16. Predictors of response to IL-2

17. Responses to immunotherapy are observed most frequently in patients with clear cell RCC 21% vs 6% alveolar >granular >papillary features

18. High Carbonic anhydrase IX expression has been associated with improved survival and a higher objective response rate in IL-2 treated patients

19. Losses of chromosomes 4, 9, and 17p as possible predictors of IL-2 nonresponse

20. Interleukin-2 before After 1 year After 1 year

21. In contrast to the results achieved with molecularly targeted therapies (eg, sorafenib, sunitinib), which lead to tumor shrinkage in most treated patients but do not produce remissions of cancer when therapy is discontinued, the administration of high-dose, bolus IL-2 consistently has produced durable responses in a small percentage of patients with advanced RCC

22. Overview of cytokine based trials for metastatic renal cell carcinoma

23. AVOREN Trial Escudier et al ASCO 2007: abs. nos. 3 IFNIFN PlaceboBevacizumab Response Rate13%31% Duration of response11 mos.13 mos. Tumour shrinkage39%70% Progression free surv.5.4 mos.10.2 mos. Overall survival19.8 mos.Not reached Grade 3/4 toxicity45%60% Discontinuation12%28%

24. What we know & what we don’t! Majority of IFN patients got 2 nd line sunitinib Majority of IFN patients got 2 nd line sunitinib How many patients who received sunitinib got 2 nd line cytokines & what were the results? How many patients who received sunitinib got 2 nd line cytokines & what were the results?

25. There is no role for Adjuvant therapy in RCC

26. Neoadjuvant Approach Rationale Success of neoadjuvant therapies in other cancers Success of neoadjuvant therapies in other cancers Assurance that patients will receive systemic treatment Assurance that patients will receive systemic treatment Potential for more rapid determination of response Potential for more rapid determination of response Response as a selection tool Response as a selection tool Ability to analyze post-treatment tissue Ability to analyze post-treatment tissue

27. Neoadjuvant Approach Advantages Select for surgery responding patients Select for surgery responding patients Downstaging Downstaging Eliminates morbidity and mortality in those that would’n benefit anyway Eliminates morbidity and mortality in those that would’n benefit anyway Harvest of treated tissue for mechanistic studies Harvest of treated tissue for mechanistic studies

28. Neoadjuvant Approach Disdvantages May add morbidity/mortality to surgery May add morbidity/mortality to surgery May decondition good surgial candidates May decondition good surgial candidates No proven benefit No proven benefit Unclear timing of surgery Unclear timing of surgery