Immunotherapy Immunotherapy in Renal Cell Cain Renal Cell Ca

F.Ghadiri M.DF.Ghadiri M.D

Radiation OncologistRadiation Oncologist

Attempts to increase Attempts to increase levels of immune levels of immune

lymphocytes capable of lymphocytes capable of recognizing cancer recognizing cancer

antigens and destroying antigens and destroying established cancers established cancers

ImmunotherapyImmunotherapy

Evidence for Tumor ImmunityEvidence for Tumor ImmunityEvidence for Tumor ImmunityEvidence 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.

Sponateous regressionsSponateous regressions

First observed 60 years agoFirst observed 60 years ago Prospective assessmentProspective assessment

7% of patients7% of patients Median duration of 2 yearsMedian duration of 2 years

Initial watchful waiting is Initial watchful waiting is appropriateappropriate Asymptomatic patientsAsymptomatic patients Low volume diseaseLow volume disease

Build this into clinical trial designBuild this into clinical trial design

Tumor-specificTumor-specific Immune Response Immune Response

Advanced RCC Advanced RCC TreatmentTreatment

Primary treatments are systemic Primary treatments are systemic therapy with molecularly targeted therapy with molecularly targeted therapy or immunotherapy therapy or immunotherapy

Surgery is palliative therapy Surgery is palliative therapy - Solitary metastatic siteSolitary metastatic site- Solitary recurrence following Solitary recurrence following

nephrectomynephrectomy- Symptoms related to bulkiness of Symptoms related to bulkiness of

disease including pain, nausea, or GI disease including pain, nausea, or GI obstruction obstruction

What have we got?What have we got? Interferon-Interferon- Interleukin-2Interleukin-2 Talactoferrin SunitinibSunitinib SorafenibSorafenib PazopanibPazopanib Bevacizumab +/- Ifn-Bevacizumab +/- Ifn- TemsirolimusTemsirolimus EverolimusEverolimus AxitinibAxitinib

VaccinesVaccines Yang JC & Childs R J Clin Oncol 2006; 24:5576Yang JC & Childs R J Clin Oncol 2006; 24:5576

Interferon-Interferon- Introduced early 1980’sIntroduced 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 thirdReduces risk of death at 1 year by one third

Survival with interferonSurvival with interferonMSKCC scoring systemMSKCC scoring system

6 months6 months >> 3 risk factors: 144 pts (22%) 1 alive 3 risk factors: 144 pts (22%) 1 alive

Risk Factors areRisk Factors are::

No prior nephrectomyNo prior nephrectomy

KPS <80%KPS <80%

Low HbLow Hb

High corrected calciumHigh corrected calcium

High LDHHigh LDH28 months28 months

0 risk factors: 164 pts (25%) 30 alive (5%)0 risk factors: 164 pts (25%) 30 alive (5%)

12 months12 months

1 or 2 risk factors: 348 pts (53%) 23 alive (4%)1 or 2 risk factors: 348 pts (53%) 23 alive (4%)

Interleukin-2Interleukin-2Protocols usedProtocols used

High dose bolus (Rosenberg)High dose bolus (Rosenberg) High dose continuous infusion High dose continuous infusion

(West)(West) Low dose bolusLow dose bolus Subcutaneous single agentSubcutaneous single agent SC combination (with IFN & 5-SC combination (with IFN & 5-

FU) (Atzpodien)FU) (Atzpodien)

A meta-analysis of trials of Interleukin-A meta-analysis of trials of Interleukin-2 in metastatic renal cell cancer2 in metastatic renal cell cancerBaaten, Voogd & Wagstaff Eur J Cancer 2004; 40:1127Baaten, Voogd & Wagstaff Eur J Cancer 2004; 40:1127

Complete responses vs routeof administration

CIV=continuous infusionSC=subcutaneous injection

BIV=intermettent bolus injection

Duration of complete remissions

ImmunotherapyImmunotherapy Immunotherapy with IL-2 activates immune Immunotherapy with IL-2 activates immune

response against RCC resulting in tumor response against RCC resulting in tumor remission rates 10-20% with median duration remission rates 10-20% with median duration of 19-109 months of 19-109 months

Severe toxicity including hypotension, Severe toxicity including hypotension, capillary leak syndrome, MI, renal capillary leak syndrome, MI, renal insufficiency, pulmonary edema, hepatic insufficiency, pulmonary edema, hepatic dysfunction, CNS dysfunctiondysfunction, CNS dysfunction

Treatment requires ICU monitoringTreatment requires ICU monitoring Used for patients that can tolerate side Used for patients that can tolerate side

effectseffects

Cytokine working partyCytokine working partyJ. Clin. Oncol. 2003 Aug 15thJ. Clin. Oncol. 2003 Aug 15th

HD IL-2 = 156 ptsHD IL-2 = 156 pts RR = 21%RR = 21%

LD IL-2 = 150 ptsLD IL-2 = 150 pts RR = 13% p=0.04 vs HDRR = 13% p=0.04 vs HD

SC IL-2 SC IL-2 RR = 10% p=0.033 vs RR = 10% p=0.033 vs

HDHD

Survival of complete responders

Predictors of response to IL-

2

Responses to immunotherapy are

observed most frequentlyin patients with clear cell

RCC21% vs 6%

alveolar >granular >papillary features

High Carbonic anhydrase IX expression has been

associated with improved survival and a higher

objective response rate in IL-2 treated

patients

Losses ofchromosomes 4, 9, and

17p as possible predictors of IL-2

nonresponse

Interleukin-2Interleukin-2

beforebefore After 1 yearAfter 1 year

In contrast to the results achieved with molecularly targeted therapies (eg, sorafenib,

sunitinib), which lead to tumor shrinkage in most treated patients

but do notproduce remissions of cancer

when therapy is discontinued, the administration of high-dose,

bolus IL-2 consistentlyhas produced durable responses

in a smallpercentage of patients with

advanced RCC

Overview of cytokine based trials for Overview of cytokine based trials for metastatic renal cell carcinomametastatic renal cell carcinoma

AVOREN TrialAVOREN TrialEscudier et al ASCO 2007: abs. nos. 3Escudier et al ASCO 2007: abs. nos. 3

IFNIFN IFNIFNPlaceboPlacebo

BevacizumabBevacizumab

Response RateResponse Rate 13%13% 31%31%Duration of responseDuration of response 11 mos.11 mos. 13 mos.13 mos.Tumour shrinkageTumour shrinkage 39%39% 70%70%Progression free surv.Progression free surv.5.4 mos.5.4 mos.10.2 mos.10.2 mos.Overall survivalOverall survival 19.8 mos.19.8 mos.Not reachedNot reachedGrade 3/4 toxicityGrade 3/4 toxicity 45%45% 60%60%DiscontinuationDiscontinuation 12%12% 28%28%

What we know & what we What we know & what we don’t!don’t!

Majority of IFN patients got 2Majority of IFN patients got 2ndnd line sunitinibline sunitinib

How many patients who received How many patients who received sunitinib got 2sunitinib got 2ndnd line cytokines & line cytokines & what were the results?what were the results?

There is no role for There is no role for Adjuvant therapy in RCCAdjuvant therapy in RCC

Neoadjuvant ApproachNeoadjuvant ApproachRationaleRationale

Success of neoadjuvant therapies in other Success of neoadjuvant therapies in other cancerscancers

Assurance that patients will receive Assurance that patients will receive systemic treatmentsystemic treatment

Potential for more rapid determination of Potential for more rapid determination of responseresponse

Response as a selection toolResponse as a selection tool Ability to analyze post-treatment tissueAbility to analyze post-treatment tissue

Neoadjuvant ApproachNeoadjuvant ApproachAdvantagesAdvantages

• Select for surgery responding patientsSelect for surgery responding patients• DownstagingDownstaging• Eliminates morbidity and mortality in Eliminates morbidity and mortality in

those that would’n benefit anywaythose that would’n benefit anyway• Harvest of treated tissue for mechanistic Harvest of treated tissue for mechanistic

studiesstudies

Neoadjuvant ApproachNeoadjuvant ApproachDisdvantagesDisdvantages

• May add morbidity/mortality to surgeryMay add morbidity/mortality to surgery• May decondition good surgial candidatesMay decondition good surgial candidates• No proven benefitNo proven benefit• Unclear timing of surgeryUnclear timing of surgery