Basic Immunology of RCC

&
Immunotherapy

Dr. Mayank Jain

Senior Resident
Department of Urology
King Georges Medical University, Lucknow
 Introduction
• Many RCCs are clinically silent until disease is either locally advanced and
unresectable or metastatic at the diagnosis

• Surgical resection of localized renal cell carcinoma (RCC) can be curative for
localized disease, but many patients eventually recur.

• Systemic therapy with anti-angiogenic treatments targeting vascular

endothelial growth factor (VEGF) is the current first line standard of care for
advanced renal cell carcinoma (RCC).

• Anti-angiogenic therapies can provide significant short term clinical benefits,

including an enhanced objective response rate (ORR) and prolonged
progression-free survival (PFS),
• Anti-angiogenic therapies typically result in treatment resistance and thus
rarely produce durable long-term response or survival.

• New therapeutic approaches based on immune mechanisms can provide

enduring responses and improve survival in the first-line treatment setting

• Clinical application of newer immunotherapies, like immune checkpoint

inhibitors (ICIs) like CTLA-4 inhibitors and PD-1 inhibitors are under
investigations .

• They act by increasing antitumor immunity by blocking native immune

regulators such as cytotoxic T lymphocyte antigen4(CTL-4) and programmed
cell death 1 (PD-1).
 Immunology in RCC
• The association between the immune system and RCC has long been
known, with evidence suggesting that RCC is an immunogenic tumor and is
associated with an innate host mediated immune response

• Removal of primary RCCs can evoke an immune response that occasionally

results in spontaneous and dramatic remissions in metastases, particularly
in the lung

• Immune system interact with tumor through various cytokines and cell
surface receptors,

• They act as molecular messengers that generate a coordinated response to

a target antigen of tumor.
Immune response to tumor antigen
• Tumors proliferate by activating pro-angiogenic pathways and at the same
time suppressing the immune response by up regulating immune
checkpoint pathways.
 Inhibitors of Tumor proliferation

1. Inhibition of the pro-angiogenic VEGF pathway by :

– VEGF inhibition (bevacizumab) or
– VEGF receptor (VEGFR) blockade (eg, tyrosine kinase inhibitor [TKI] such as
sunitinib , pazopanib ,axitinib, lenvatinib , and cabozantinib.
Thought to normalize tumor vasculature, facilitate lymphocyte trafficking,

and ultimately promote lymphocyte infiltration of tumors.

2. Immune checkpoint inhibition:

– Anti–PD-1 (programmed cell death 1) or anti–PD-L1 (programmed cell death 1
ligand 1) antibodies
– Anti–CTLA-4 (cytotoxic T lymphocyte antigen 4) antibodies
These results in T-cell priming, activation, and finally T-cell–mediated tumor cell
death.
 Mechanisms of Immune Supression by tumor and
basis of Immunotherapy

• Altering Tumor antigens – alteration or lose the expression of antigens on

tumor cell

• Altering Immune checkpoint pathways – Tumors can express ligands that

are recognized by inhibitory receptors on effector T cells, such as CTLA-4,
PD-1, and LAG-3.

• Recruitment of immune cells – inhibition of recruitment of regulatory T

cells and myeloid-derived suppressor cells
 Immune Checkpoint pathways

• CTLA-4 is a checkpoint molecule • PD-1 is another checkpoint molecule expressed

expressed on activated T cells. on effector T cells.
• CD80/86 on the antigen-presenting cell • Acts as a negative regulator of immune response.
is the ligand for CTLA-4. • Binding of PD-1 to its ligands, PD-L1 and PD-L2,
• Binding of this receptor–ligand pair inhibits T-cell activity.
downregulates T-cell activity. • RCC overexpress PD-L1 to defend against an
immune response.
 Immunotherapy
Interleukin -2:
• Interleukin-2 (IL-2) is a naturally occurring cytokine having multiple immuno-regulatory
properties.

• Interleukin-2 used to treat mRCC with response rates ranging from 7-27% .

• IL-2 can be administered as high-dose intravenous bolus (IL-2 is FDA approved) or

continuous intravenous infusion, and at lower doses subcutaneously.

• The optimal dosing regimen is not well established

• IL-2 combined with other active agents such as alpha-interferon and chemotherapy,
although it is not clear if these combinations provide additional benefit.
• Toxicity — includes hypotension, cardiac arrhythmias, metabolic acidosis,
fever, nausea and vomiting, dyspnea, edema, oliguria and renal failure,
neurotoxicity, and dermatologic complications.

• High-dose IL-2 is the only therapy of inducing durable complete remissions

and potential cures.

• However, its toxicity profile makes this approach realistic for very carefully
selected young patients with an excellent performance status, limited
extent of metastases, and no significant comorbidities.
Alpha-interferon
• A naturally occurring cytokine

• Has anticancer activity in both RCC and superficial bladder cancer.

• Clinical responses in up to 20% of patients.

• In contradistinction to IL-2 as a single agent, durable complete responses are

quite rare.

• The addition of bevacizumab to alpha-interferon is superior to alpha-

interferon alone.

• The use of interferon-alfa (IFNa) has largely been replaced by immunotherapy

with checkpoint inhibitors and molecularly targeted agents, except in
combination with bevacizumab.
 Immune Checkpoint Inhibitors
Programmed Death-1 Inhibitors (PD-1):
Nivolumab
• Fully humanized PD-1 blocking antibody.

• Promising and durable responses have been reported in phase I and II

studies in melanoma, non small-cell lung cancer, and, more recently, renal
cell cancer

• Programmed cell death 1 (PD-1) inhibitor, has been approved as second-line

therapy following antiangiogenic targeted treatment for advanced RCC .

• Based upon improvement in overall survival (OS) in a phase III trial, the
combination of nivolumab plus ipilimumab (an anticytotoxic T lymphocyte
associated protein 4 [CTLA-4] antibody) in treatment-naïve patients.
Dose —

• Nivolumab was originally approved at a dose of 3 mg/kg every two weeks

based upon the phase III CheckMate 025 trial.

• An alternative schedule of nivolumab 480 mg every four weeks was

approved based upon pharmacokinetic data
Pembrolizumab —
• Single-agent checkpoint inhibitor immunotherapy being studied in the
KEYNOTE-427 trial.

• 110 patients with advanced or metastatic clear cell RCC were treated with
pembrolizumab (200 mg every three weeks).

• All patients had measurable disease and had not received prior systemic
therapy.

• Preliminary results were :At a median follow-up of 12 months,

• Overall objective response rate was 38 percent,

• Disease control rate was 69 percent.

• The response rate was higher in patients with intermediate-risk/poor-risk
disease compared with those with favorable-risk disease (42 versus 32
percent)

• The response rate was higher in those with increased expression of PD-L1
of ≥1 percent versus those with PD-L1 expression <1 percent
Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) Antibody:
Ipilimumab:
• Monoclonal antibody directed against CTLA4.

• Phase II study of ipilimumab in metastatic RCC, 5 of 40 responses were

noted in the higher dose group (3mg/kg every 3 weeks) compared to 1 of
21 responses in the lower dose group (3mg/kg followed by 1mg/kg every 3
weeks).

• Though all responses were partial, patients who had failed IL2 also
responded

• There are currently no other studies of single agent ipilimumab in RCC and
the ongoing trials are evaluating the efficacy of combining ipilimumab with
PD-1blockade in RCC.
• A phase III study of ipilimumab and the anti-PD-1 antibody nivolumab
versus sunitinib is currently ongoing with previously untreated advanced
or metastatic RCC (CheckMate214).
 Combination Immunotherapy

Nivolumab plus ipilimumab —

• In patients with advanced RCC, the combination of nivolumab plus ipilimumab

demonstrated a survival benefit and favorable toxicity relative to sunitinib.

• In the phase III CheckMate 214 trial, with previously untreated, advanced or
metastatic, clear cell RCC were randomly assigned to nivolumab plus ipilimumab
versus sunitinib.

• Patients with brain metastasis and previous exposure to targeted therapy or a

checkpoint inhibitor were excluded.

• The combination of nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) was given

every three weeks for four doses, followed by single-agent nivolumab (3 mg/kg)
every two weeks.
• Sunitinib was given at 50 mg per day for four weeks out of every six-week
cycle.

• For the entire intention-to-treat study population,

– OS was significantly increased with nivolumab plus ipilimumab
– The objective response rate was also significantly increased (39 versus 32%),
– no difference in PFS (median 12.4 versus 12.3 months, HR 0.98).

• For patients with intermediate- or poor-risk disease,

– Significant improvement in OS and in the objective response rate (42 versus 27 %).
– Median PFS was increased as well, but it did not reach statistical significance (11.6
versus 8.4 month)
• PFS and response benefit appeared to be enhanced in patients with tumors
having PDL1 expression ≥1 percent.

• In intermediate- or poor-risk disease and tumor PD-L1 expression ≥1 percent,

the benefit with the combination was more pronounced (objective response
rate 58 versus 25 percent, median PFS 22.8 versus 5.9 months).

• In intermediate-or poor-risk disease and tumor PD-L1 expression <1 percent,

OS was significantly increased. But no significant difference between the
combination and sunitinib in either the objective response rate (37 versus 28
percent ) or PFS (median 11 versus 10.4 months).
• In favorable-risk disease, the response rate was lower with the combination
of nivolumab plus ipilimumab compared with sunitinib (29 versus 52
percent), and PFS was shorter (median 15.3 versus 25.1 months)

• Side effects and quality of life data also favored the combination of
nivolumab plus ipilimumab over sunitinib

• The combination of nivolumab and ipilimumab is approved by the US Food

and Drug Administration (FDA) for the treatment of intermediate- and poor-
risk, previously untreated patients with advanced RCC, and it is incorporated
into the European Association of Urology guidelines.
Axitinib plus pembrolizumab —

• The antiangiogenic agent axitinib has been shown to combine effectively

and safely with the checkpoint inhibitor pembrolizumab.

• In the phase III KEYNOTE-426 trial, with previously untreated, advanced,

clear cell RCC were randomly assigned to pembrolizumab plus axitinib
versus sunitinib alone.

• After a median follow-up of 13 months, pembrolizumab plus axitinib

resulted in the following:
– Improved OS (90 versus 78 percent at 12 months).
– Longer PFS (median 15.1 versus 11.1 months).
– Superior objective response rates (59 versus 36 percent).
– Numerically higher rates of grade 3 or higher adverse events (76 versus 71 %).
– In both groups, the most common adverse events were diarrhea and hypertension .
• These benefits were seen regardless of PD-L1 expression and regardless of
International Metastatic Renal Cell Carcinoma Database Consortium
(IMDC) risk classification.

• The data from this trial led to approval by the US FDA of pembrolizumab
plus axitinib for the first-line treatment of patients with advanced RCC

• NCCN panel has included axitinib + pembrolizumab as a category 1

preferred regimen option for first-line treatment of ccRCC in poor- and
intermediate-risk patients, and a category 2A preferred regimen option for
first-line treatment of ccRCC in favorable-risk patients.
Axitinib plus avelumab —

• Axitinib has shown to combine safely and effectively with the checkpoint
inhibitor avelumab, and this is an option for first-line therapy.

• In the phase III JAVELIN Renal 101 trial, treatment-naïve patients with
advanced clear cell RCC were randomly assigned to the combination of
avelumab and axitinib versus sunitinib

• Axitinib plus avelumab improved median PFS in the overall group (13.8
versus 8.4 months) and among those with PDL1 positive tumors (13.8
versus 7.2 months).
• The combination did not demonstrate an improvement in OS .

• In randomized trials, axitinib plus avelumab improved PFS, but not OS,
relative to sunitinib,

• Whereas both survival outcomes were improved and simultaneously

evident for the other two combination regimens.

• Grade ≥3 toxicities were similar between the two groups.

• Based on the available data and FDA approval, axitinib + avelumab are
listed in the NCCN Guidelines as a category 2A other recommended option
as first-line treatment across all risk groups for patients with previously
untreated stage IV ccRCC.

• However, the preferable regimen is either nivolumab plus ipilimumab or

axitinib plus pembrolizumab over axitinib plus avelumab for patients
without a contraindication to immunotherapy.
Atezolizumab plus bevacizumab —

• Phase III randomized trial IMmotion 151 trial, with previously untreated
patients with advanced or metastatic RCC to either atezolizumab plus
bevacizumab or to sunitinib

• The trial included patients with favorable-risk (20 percent), intermediate-

risk (70 percent), and poor-risk (10 percent) RCC. PD-L1 expression was ≥1
percent in 40 percent.

• In the overall intention-to-treat population, median PFS, , was longer with

the combination than with sunitinib (median 11.2 versus 8.4 months).

• The objective response rates with the combination and with sunitinib were
37 and 33 percent, respectively..
• In the PD-L1 positive patients, median PFS, was longer with atezolizumab
plus bevacizumab than with sunitinib (median 11.2 versus 7.7 months).

• The objective response rate with the combination was 43% compared
with 35 %, with sunitinib.

• In the PD-L1 positive population, atezolizumab plus bevacizumab trended

numerically towards improved OS, but the results were not statistically
significant (HR 0.84, 95% CI 0.62-1.15).
 OTHER IMMUNOTHERAPY APPROACHES

Vaccines —
• Novel approaches to re-engage immune recognition of tumor through
autologous cellular immunotherapy are under active development in
advanced RCC patients.

• They are designed to enhance innate or adaptive immunity depending on

the antigen and vehicle.

• Examples include autologous tumor cell vaccines, dendritic cell (DC) based
vaccines, and peptide based vaccines.

• Results from ongoing trials of DC vaccines in RCC are the most promising
in RCC
• DCs play a critical role in producing antitumor immunity.

• AGS-003 (rocapuldencel-T), an autologous DC immunotherapy in which

the DCs are coelectroporated with amplified tumor RNA plus synthetic
CD40L RNA.

• Ongoing Phase III ADAPT study (NCT01582672) patients with metastatic

RCC undergoing debulking nephrectomy are randomly assigned to
sunitinib or sunitinib plus AGS-003 (eight intradermal injections in the first
year followed by boosters every three months.) Results Awaited

• In another approach, a cancer vaccine IMA901 based upon tumor-

associated peptides as first-line therapy to patients with metastatic RCC
who were HLA-A*02 positive.
 Choice of therapy and Recommendations for Management of
Advanced/metastatic disease:

Role of surgery and local therapy:

• CN is recommended in patients with good PS [I, A] except in intermediate-
and poor-risk patients with asymptomatic primary tumours when medical
treatment is required [I, A]

• CARMENA and SURTIME investigated the role and sequence of CN

• CARMENA demonstrated that upfront CN should no longer be considered the

standard of care in intermediate- and poor-risk patients with asymptomatic
primary tumours when medical treatment is required [I, A].

• Secondary CN in patients with local symptoms due to the primary tumour or

near complete responses to systemic therapy remains an option.
• Recommendation: For patients with metastatic disease at presentation
who are candidates for immunotherapy, debulking nephrectomy prior to
treatment when it is clinically feasible and justifiable (good performance
status, 75 percent debulking possible, no symptomatic metastatic disease)
before initiating systemic therapy (Grade 2C).
Systemic treatment for ccRCC:

• The introduction of immunotherapies and immunotherapy/TKI

combinations have given patients with ccRCC more options in the frontline
treatment setting.

• Recommendations mainly relate to clear cell histology, since most of the

pivotal trials have been conducted in this common histological subtype.

• Recommendations are based according to risk stratification.

• The choice of treatment for patients with advanced disease should

consider prognostic risk factors
 Risk stratification
• NCCN panel emphasized the use of prognostic risk models to guide treatment
selection in clinical practice.

• The International Metastatic Renal Cell Carcinoma Database Consortium

prognostic model integrates six adverse factors

– Karnofsky performance status (KPS) <80 percent

– Time from diagnosis to treatment <1 year
– Hemoglobin concentration <lower limit of normal
– Serum calcium >upper limit of normal
– Neutrophil count >upper limit of normal
– Platelet count >upper limit of normal

Stratification:
• none of these risk factors - good risk,
• one or two risk factors - intermediate risk,
• three or more risk factors - poor risk.
 Kidney Cancer, Version 2.2020
NCCN Guidelines
Recommendations:
• Systemic therapy is the preferred initial treatment option for patients with
stage IV disease who have any poor-risk features, clear cell histology, and
high-volume distant metastases, instead of cytoreductive nephrectomy
followed by systemic treatment

• This recommendation is based on results of the non-inferiority phase III

CARMENA trial.

• Sunitinib alone was non-inferior to sunitinib after nephrectomy, with a

median overall survival (OS) of 18.4 versus 13.9 months),

• Analysis by risk group also showed longer median OS for sunitinib alone
compared with sunitinib after nephrectomy.
 NCCN GUIDELINES Version 2.2020 …..

• Patients with excellent performance status and small-volume distant

metastases could be considered for cytoreductive nephrectomy followed
by systemic treatment.

• Patients with a resectable primary RCC and synchronous oligometastatic

disease can be managed with either surgical metastasectomy, stereotactic
body radiation therapy, or ablative techniques.

• In patients with unresectable disease the panel recommends performing

tissue sampling to determine histology and guide subsequent
management
EAU Guidelines
 ESMO Guidelines:
First line therapy:

Good-risk patients:
– VEGF-targeted agents should remain the standard of care with sunitinib,
pazopanib or bevacizumab combined with IFN.

– Tivozanib is another standard of care when available.

Intermediate-risk patients:

– combination of nivolumab and ipilimumab is the new standard of care.

– If this combination is not available, VEGF-targeted agents should be
recommended as in good-risk patients, with cabozantinib being another
option in this patient population.
 Poor-risk patients:
• Combination of nivolumab and ipilimumab is the new standard of care.
• cabozantinib is an attractive option when available.
• In this specific patient population, temsirolimus remains an option, as well
as TKIs (sunitinib or pazopanib)
Second line therapy:
Third line therapy:

• In patients already treated with two TKIs, either nivolumab or cabozantinib

is recommended.If neither of these drugs is available, everolimus remains an
acceptable option.

• In patients previously treated with one TKI and nivolumab, cabozantinib is

recommended, if available. In the absence of cabozantinib, either
everolimus or axitinib can be used.

• In patients previously treated with one TKI and cabozantinib, nivolumab is

recommended, and either everolimus or axitinib remain acceptabl options.
• In patients previously treated with VEGF-targeted therapy and an mTOR
inhibitor, sorafenib has shown activity .

• However, nivolumab or cabozantinib can be recommended in this setting.

Finally, another TKI or re-challenge with the same TKI is considered as an
option.
Medical treatment for non-ccRCC
Some specific situations should be considered:

• In papillary RCC with cMET mutation Crizotinib or other cMET inhibitors

such as cabozantinib appear as an acceptable option instead of the usual
VEGF TKIs.

• Patients with chromophobe RCC may benefit from mTOR inhibitors since
mutation on chromosome 7 was shown to lead to a loss of the folliculin
gene with upregulation of mTOR .

• Sarcomatoid tumours are very inflamed tumours, usually with poor-risk

features, and are sensitive to immune checkpoint inhibitors. Thus, the use
of nivolumab/ipilimumab combination should be considered as a good
option for these patients
• CDCs (and also medullary carcinomas) were reported to behave more like
aggressive urothelial tumours rather than RCCs and may therefore be
considered for chemotherapy, although expected results are still poor.
 Immune-Related AEs
• As sequelae of increased immune activity, a unique spectrum of
inflammatory adverse effects, which are termed immune-mediated adverse
reactions or immune-related AEs (irAEs), are associated with ICI treatment
(alone or in combination regimens).

• Onset can be unpredictable, but they typically start within the first few weeks
to months after treatment initiation and may occur even after drug
discontinuation

• Usually, irAEs are mild and transient. However, they may occasionally be
more severe, especially with combination therapies.

• Early recognition, close monitoring, and prompt intervention are critical to

their successful management.
• Depending on the type and severity of the irAE treatment interruption
and/or use of immune-modulating drugs (corticosteroids and/or tumor
necrosis factor inhibitors) is often recommended.

• Typically, high-dose prednisone treatment (or equivalent to 40 mg/d) is

administered until the toxic effec is downgraded, followed by a slow taper
over 4 to 6 weeks.

• Restarting treatment is generally contraindicated for higher-grade life-

threatening toxic effects.

• For non–life-threatening events, retreatment may be feasible in some

patients; however, an increased risk for recurrence or manifestation of
new irAEs exists.