Journal of Kidney Cancer and VHL 2014; 1(7): 74-83. Doi: http://dx.doi.org/10.15586/jkcvhl.2014.18
Review
Article
Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a Still-Viable Option?
1Divisions of Immunotherapy and Medical Oncology, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina, USA; 2Divisions of Surgical Oncology and Immunotherapy, Levine Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina, USA.
Abstract
Modulation
of the immune response plays an important role in the natural history of renal
cell carcinoma. Spontaneous regression
of metastases has been well documented in a small percentage of patients after
they undergo de-bulking nephrectomy without any additional systemic
intervention. The only logical
explanation for these observations is “resetting” of the balance between tumor
and the host immune system that, having been overwhelmed by the tumor burden,
is able to function better after tumor de-bulking. Attempts to modulate the activity of the
immune system “on demand” have included the use of vaccines,
cytokines/lymphokines, adoptive cell transfer, monoclonal antibodies and most
recently manipulation of immune checkpoint inhibitors. Here we review the data for infusional
interleukin-2 in the management of advanced renal cell carcinoma and its role
in current clinical practice. Copyright: The Authors.
Received: 11
November 2014; Accepted
after revision: 19 November 2014; Published: 23 November 2014
Author
for correspondence: Dr.
Asim Amin MD, PhD, Divisions of Immunotherapy and Medical Oncology, Levine
Cancer Institute, Carolinas Medical Center, Charlotte, North Carolina, USA. E-mail: [email protected]
How
to cite: Amin
A, While RL. Interleukin-2 in Renal Cell Carcinoma: A Has-Been or a
Still-Viable Option? Journal of Kidney Cancer and VHL 2014; 1(7): 74-83. DOI: http://dx.doi.org/10.15586/jkcvhl.2014.18
Introduction
Interleukin-2
Demonstration that T lymphocytes could be grown in vitro, only in the
presence of conditioned medium from phytohemagglutinin (PHA)-stimulated human
blood lymphocytes (4), led to the discovery of a T cell growth factor subsequently
designated IL-2 (5,6,7).
T lymphocytes grown in IL-2 containing culture were shown to have the
ability to kill tumor cells in vitro (8).
IL-2 activated human peripheral blood lymphocytes showed lysis of
natural killer-resistant fresh solid tumor cells - these were termed LAK cells
(9). IL-2 was deemed to be necessary and
sufficient for T cell growth and activation.
In vivo animal studies demonstrated that adoptive immunotherapy with
transfer of syngeneic LAK cells generated in vitro, using IL-2, could eliminate
natural, killer-resistant, established pulmonary melanoma and sarcoma
metastases (10, 11). IL-2 was shown to
stimulate in vivo proliferation of adoptively transferred LAK cells (12), and
systemic administration of high-dose IL-2 without adoptive T cell transfer was
shown to cause regression of established pulmonary metastases and subcutaneous
tumors, proving that LAK cells could be generated in vivo (13). The cDNA coding
for IL-2 was cloned and was shown to consist of 153 amino acids with a
molecular weight of 15,420 daltons (14).
Availability of IL-2 in large quantities made clinical trials
possible. Rosenberg et al. reported
their experience in 25 treatment-resistant patients with advanced cancer, who
were treated with a combination of LAK cells and interleukin-2. These included patients with malignant
melanoma, colorectal cancer, sarcoma, renal cell carcinoma, non-small cell lung
cancer and esophageal cancer. Eleven out
of 25 patients had marked tumor regression; one patient with metastatic
melanoma had a complete remission while 10 partial responses were observed,
thus establishing proof of the principle that manipulation of the immune system
using high-dose IL-2 could be performed safely and would induce significant
clinically relevant responses (15).
The discovery and availability of IL-2 for clinical use was pivotal in
bringing an immunotherapeutic modality to the forefront (16). Given that immune-mediated regression had
been observed in patients with renal cell carcinoma and the fact that renal
cell carcinoma does not respond to chemotherapy, the earliest clinical
investigations with IL-2, carried out at the NIH Surgery Branch, included renal
cell carcinoma. A progress report on the
treatment of 157 patients with advanced cancer, using LAK cells and IL-2 or
high-dose IL-2 alone, included 36 patients with renal cell carcinoma. An impressive 33% response rate was observed:
4/36 had a complete response and 8/36 had a partial response (≥ 50% decrease in
sum of the products of the perpendicular diameters of all lesions). An additional 7/36 patients experienced a
minor response (25 to 49% decrease in sum of the products). Most of the patients who had a complete
response had lung metastases (17).
High-dose
IL-2 in RCC
Further work at the NCI Surgery Branch reported their experience in 283 patients with metastatic melanoma or metastatic renal cell cancer treated from September 1985 through December 1992 with high-dose bolus IL-2– this series included 149 patients with renal cell carcinoma. Patients received IL-2 at the dose of 720,000 international units per kilogram intravenously every 8 hours for a maximum of 15 doses per cycle: 2 cycles constituted a course of therapy. Patients who showed response or stable disease after the first course went on to receive additional therapy. An overall response of 20% (CR+PR) was observed in patients with renal cell carcinoma, 7% (n=10) achieved complete response, and 13% (n=20) had a partial response. With the exception of one complete responder who had liver metastases, all others had lung metastases or involvement of lymph nodes. The responses were noted to be durable and ongoing at up to 76 months in the patients with a complete response, and 69 months in those with a partial response at the time of publication. There were 3 (1.1%) treatment-related deaths; 2 due to myocardial infarction and one as a result of sepsis (18).
Table 1. High dose interleukin-2 in advanced RCC
Study |
N |
Dose |
ORR |
Response Duration (Months) |
Ref. |
7 phase II studies |
255 |
600,000-720,000
IU/kg |
ORR*=
15% CR= 7% PR= 8% |
54 (3 to 131+) 80+ (7
to 131+) 20 (3
to 126+) |
(19,20) |
NCI experience Single Institution |
259 |
720,000IU/kg |
20% CR=9% PR =11% |
21 CR median survival
not reached – 221+ |
(21) |
Phase II “SELECT” study |
120 |
600,000IU/kg |
29% |
20
responders (4 to 35+) |
(22) |
* CR, complete response; ORR, overall response rate; PR, partial response
Some of the selected trials using high-dose IL-2 are summarised in Table
1. A large additional series published by Fyfe et al. reported the outcomes of
255 patients with advanced renal cell carcinoma treated with high-dose bolus
IL-2 enrolled in 7 phase II studies at 21 institutions. Two of these studies used the dose of 720,000
international units per kilogram while the other 5 used the dose of 600,000
international units per kilogram administered every 8 hours over 15 minutes for
a total of 14 doses per cycle. Responses
were observed in 37/255 patients (15%); 17 (7%) patients achieved a complete
response and 20 patients (8%) a partial response. The updated median duration of response for
all patients was 54 months. The median
duration for those with complete response had not been reached at the time of
reporting: it was at least 18 months with a range of 7 to greater than 131
months. The median duration of response
for the patients who had a partial response was 20 months with a range of 3 to
greater than 126 months. Eleven (4%) out
of 255 patients died of treatment-related toxicity (6 patients had a myocardial
infarction or respiratory failure, 3 had gastrointestinal toxicity, one had
sepsis and one died at home of unknown causes) (19, 20).
Klapper et al. reported the expanded NCI Surgery Branch experience for
259 patients with advanced renal cell carcinoma who were treated between 1986
and 2006 with high-dose IL-2 at the dose of 720,000 units per kilogram IV bolus
every 8 hours up to a total of 15 doses per cycle (later reduced to a maximum
of 12 doses). Response was evaluated
using the WHO criteria initially and RECIST criteria since 1998. An overall objective response rate of 20% was
observed (consistent with previous reports); 9% (23/259) of patients achieved a
complete response and 12 % (30/259) of patients had a partial response. Median survival for the partial responders
was 39.1 months and had not been reached for the complete responders at the
time of analysis. There were 2
treatment-related deaths in the earlier part of the study (21).
In an effort to optimize IL-2 therapy, the renal cell “SELECT” trial was
designed to assess if the patient population could be selectively enriched
based on carbonic anhydrase IX overexpression within the tumor besides other
factors. Of the 120 patients treated in
this study, 96% had clear cell histology and 99% had nephrectomy. Patients received high-dose IL-2 at the dose
of 600,000 international units per kilogram every 8 hours. The overall response rate was 29% (35/120):
the response rate for clear cell histology was 30% (35/115). A complete response was observed in 7
patients, while 28 patients had a partial response. Although no correlation was noted with
carbonic anhydrase IX expression, clear cell histology appeared to be important
given the higher than historically observed response rates (22).
High dose
vs/or low dose IL-2
Despite the durable responses elicited by high-dose IL-2 that may translate into “cure” for some, its use is restricted to selected individuals with good organ function and performance status. Wider applicability is limited due to significant toxicity in the form of a brisk capillary leak syndrome that can result in multi-organ system compromise, albeit rapidly reversible but requiring intense monitoring and trained personnel in place. Efforts have therefore been made to study the efficacy of IL-2 at lower doses in the hope that treatment might be safer and easier to administer to a broader patient base. Some of the selected trials using low-dose IL-2 and comparing them to high-dose regimens are discussed (Table 2).
Table 2. High
dose interleukin-2 vs/or low dose interleukin-2 in advanced RCC
Study |
N |
Dose |
ORR |
Response Duration (months) |
Ref. |
Randomized
|
|
|
|
|
(23) |
Randomized |
|
|
|
|
(24) |
Randomized
|
|
|
|
|
(25) |
Randomized
|
|
9x106 IU 3x/w
IL2 and IFN schedule as above; IFN dose 6x106IU |
|
|
(26) |
* CIV, intravenous; CR, complete response; ORR,
overall response rate; OS, overall survival; PR, partial response; Sc,
subcutaneous
In that vein, Negrier et al. reported 425 patients with metastatic renal
cell carcinoma, randomized to receive IL-2 as a continuous intravenous infusion
or interferon alpha 2a or the combination of both (23). In the IL-2 monotherapy arm induction phase,
drug was administered at the dose of 18 million international units per square
meter of body surface area per day for 5 days repeated twice with a 6-day
break. In the maintenance phase, the
same dose was repeated every 3 weeks. In
the interferon monotherapy arm, drug was administered at the dose of 18 million
international units subcutaneously 3 times a week for 10 weeks as induction and
13 additional weeks as maintenance. In
the combination arm, IL-2 was administered at full dose (as above) but
interferon alpha 2a was administered at the dose of 6 million international
units 3 times a week during IL-2 dosing.
The response rates were 6.5% for low dose IL-2 monotherapy, 7.5% for
interferon alpha 2a monotherapy and 18.6% for the combination. There was no significant difference in
overall survival, and toxicity was greater in the IL-2 containing arms.
The Surgery Branch at the NCI conducted a 3 arm randomized study
comparing high-dose IL-2 to two different low-dose IL-2 regimens (24). A total of 156 patients were assigned to the
high-dose arm and received IL-2 at the dose of 720,000 international units per
kilogram IV bolus every 8 hours.150 patients received low-dose IL-2 at the dose
of 72,000 international units per kilograms IV bolus every 8 hours, while 94 patients
in the third arm received daily subcutaneous low-dose IL-2The response rate in
the high-dose arm was 21%, 13% in the low-dose intravenous arm, and 10% in the
daily subcutaneous. There were no
treatment-related deaths. Toxicities,
especially hypotension, were less frequent in the low-dose arms. Durable responses were noted in all arms:
8/11 patients who achieved a complete response in the high-dose arm were noted
to have an ongoing response at 9.3 years. Three of the 6 patients who achieved
complete response in the low-dose intravenous arm were noted to have ongoing
response at 10.1 years and one complete response in the subcutaneous low-dose
arm had an ongoing response past 78 months at the time of analysis.
The Cytokine Working Group further conducted a randomized phase III
study to compare high-dose IL-2 with the combination of low-dose subcutaneous -
IL-2 and interferon (25). In this study
91 patients received outpatient subcutaneous IL-2 at a loading dose of 5
million units per body meter squared every 8 hours for 3 doses on day 1
followed by 5 million units per meter squared on days 2, 3, 4 and 5 during the
first week and then 5 million units per body meter squared for 5 days every
week for 3 weeks. In addition these
patients received interferon at the dose of 5 million units per meter squared
thrice weekly for 4 weeks. A total of 95
patients were treated on the high-dose intravenous IL-2 arm and received
600,000 units per kilogram IV bolus every 8 hours for a maximum of 14
doses. An overall response of 23.2%
(22/95) was observed in the high-dose intravenous IL-2 arm compared to 9.9%
(9/91) in the low-dose subcutaneous IL-2 plus interferon arm. Eight patients achieved a complete response
in the high-dose intravenous IL-2 arm; this response was durable in 7/8
patients at 3 years. Three of 9
responding patients achieved a complete response in the low-dose subcutaneous
IL-2 plus interferon arm, but all of them had recurrence of disease within 3
years.
The French immunotherapy intergroup conducted a randomized trial to
compare low dose subcutaneous IL-2,
interferon alpha 2a, the combination of
the 2 cytokines and medroxyprogesterone in 492 patients with metastatic
renal cell carcinoma of intermediate prognosis (26). Intermediate prognosis was defined by
requiring a Karnofsky score of ≥80% if metastases in more than one organ;
Karnofsky score of 80% if metastases in one organ; normal blood, liver and
renal function. Patients with prior
treatment, evidence of brain metastasis, uncontrolled cardiac issues, active
infections or who were on corticosteroids were excluded. Subcutaneous IL-2 was administered at the
dose of 9 million international units every day to 125 patients. 122 patients
received interferon alpha 2a at the dose of 9 million international units 3
times a week. 122 patients received both interferon and IL-2 at the above
doses, and 123 patients received medroxyprogesterone acetate at the dose of 200
mg every day. The response rate was 3.3%
in the IL-2 arm, 3.5% in the interferon arm, 10.9% in the cytokine combination
arm, and 1.7% in the medroxyprogesterone arm.
No differences were noted in the progression-free survival or overall
survival amongst all the arms.
High Dose
IL-2 – Contemporary Experience: “PROCLAIM”
Based on the relatively poor results associated with low-dose IL-2
high-dose IL-2 has generally come to be accepted as the standard of care for
properly selected patients. Since the early trials that led to the approval of
high dose IL-2 centers of excellence have developed treatment schema that can
greatly reduce toxicities. Mitigation
strategies and guidelines to safely administer high-dose interleukin-2 have
since been developed and used effectively (27). Data from contemporary single-institution/group
series show that high-dose IL-2 can be administered safely at centers with
adequate experience and careful selection of patients. At the Levine Cancer Institute, we have
treated 104 patients with advanced renal cell carcinoma with high-dose IL-2.
The response rate has been 26% including 8 complete and 19 partial
responses. Five of the 8 complete
responders have an ongoing response at 122 months. There has been no treatment-related
mortality (28). Roswell Park Cancer
Institute reported their experience for 91 patients who were treated with
high-dose IL-2. The overall response
rate was 16% with no treatment-related mortality (29). Payne et al. reported
the experience from the Earle A Chiles Research Institute for 186 patients with
advanced renal cell cancer treated with high-dose IL-2. The overall response rate was 24% with
treatment-related mortality of less than 1% (30). The numbers treated at
individual centers are however modest, making these non-systematic reviews
difficult to interpret. In order to
capture the contemporary experience more effectively, a high-dose IL-2 registry
was established incorporating 35 centers in the USA (31). PROCLAIM (Proleukin(R)
Observational Registry to Evaluate the Treatment Patterns and Clinical Response
in Malignancy) is designed to create a robust observational database of real
world contemporary high-dose IL-2 experience.
The goals of the PROCLAIM registry are to: (i), provide information
regarding IL-2 and its prospective use; (ii), compare the difference in
administration approaches for their respective effect on outcomes; (iii), validate
efficacy of high-dose IL-2 on response and survival in the treatment of
malignant diseases; (iv), identify patients and site-specific prognostic
factors and (v), study and potentially guide the emergence of new therapeutic
options in the immunological armamentarium.
The registry started enrolling the prospective cohort in September 2011;
data for a retrospective cohort was collected between January 2007 and February
2012.
Despite the compelling high dose IL-2 data, many oncologists now employ
targeted therapy with suppression of the VEGF or mTOR pathways as initial
therapy in patients with advanced renal cell carcinoma. Retrospective reports with small numbers of
patients treated with high-dose IL-2 after treatment with targeted therapy
suggest higher than expected cardiovascular toxicity (some quite profound
including cerebral vasculitis) if patients have previously received
VEGF-targeted therapy (32). The PROCLAIM
registry was queried to address the question of optimal sequencing of IL-2
therapy with targeted therapy.
Observations from the retrospective data cohort presented by Morse et
al. (33) showed the median overall survival for patients (n=82) who received
high-dose IL-2 as initial systemic treatment to be 61.8 months compared to 48
months for those (n=15) who had received
targeted therapy prior to high-dose
(IL-2). While not conclusive,
this observation suggests superior results in patients treated with high dose
IL2 as first line therapy.
Discussion
Immunotherapy with high-dose IL-2 had been the mainstay of systemic
treatment for advanced renal cell carcinoma until the development of agents
inhibiting the VEGF and mTOR pathways.
VEGF TKIs (sunitinib, pazopanib, axitinib, sorafenib), mTOR inhibitors
(temsirolimus, everolimus) and the combination of bevacizumab plus interferon
have been approved for treatment of patients with metastatic renal cell
carcinoma by the US FDA (34).
Availability of these agents has had an impact on the natural history of
the disease with prolongation of median survival to 22 months (35). Durable long-term responses observed with
immunotherapy have, however, rarely been reported with these agents.
Given that treatment with high-dose IL-2 is not applicable for many
patients with advanced renal cell carcinoma, new immunotherapeutic approaches
are being investigated. Nivolumab is a fully human antibody that binds to PD-1,
an immune inhibitory checkpoint expressed on the surface of T cells. Binding of the anti-PD-1 antibody to PD-1
blocks the interaction with its ligands PD-L1 and PD-L2 and prevents the T
effector cell from switching off (36, 37).
A phase II trial of nivolumab monotherapy in patients with metastatic
renal cell carcinoma showed an overall response rate of 20% (using RECIST
criteria v1.1) in heavily pretreated patients who had received up to 3 prior
lines of treatment. The median overall
survival for patients having received more than 2 lines of prior treatment was
18.7 months and was not reached in patients who had received one prior line of
therapy. Almost one third of the
responding patients showed ongoing responses beyond 24 months. Patients’ overall tolerance was reported to
be good with grade 3-4 treatment-related ‘select’ events (defined as having
potential immunologic etiology that require frequent monitoring and/or unique
intervention) observed in less than 5% of the patients (38).
Hammers et al. presented data from a phase I study with the combination
of nivolumab plus ipilimumab in patients with metastatic renal cell
carcinoma. Ipilimumab is a fully
humanized IgG1 antibody that binds to the immune inhibitory checkpoint
CTLA-4. Binding of anti-CTLA-4 antibody
to CTLA-4 expressed on the surface of activated T cells prevents the T cell
from switching off (39). Ipilimumab has
been approved for treatment of patients’ metastatic melanoma (34). Almost 80% of the patients in the study had
received at least one prior line of treatment prior to receiving the
combination. The overall response rate
for nivolumab at 3mg/kg and ipilimumab 1 mg/kg was 43%: 78% of the responders
had ongoing responses at the time of analysis (24 weeks). The combination of the two drugs was
tolerated well with treatment-related ‘select’ adverse events (defined as
above) observed in less than 5% of the patients (40). Amin et al. reported data for the phase I
study with the combination of nivolumab with either sunitinib or pazopanib in
patients with metastatic renal cell carcinoma.
The overall response rate was 52% and 45% in the sunitinib and pazopanib
combination arms respectively. While
there were no treatment-related deaths, 82% in the sunitinib arm and 70% in the
pazopanib arm experienced grade 3-4 treatment-related toxicities (41). These immunotherapeutic approaches hold great
promise but mature data addressing the durability of these responses is
awaited.
Conclusion
Where does standard high-dose interleukin-2 fit in clinical practice
with currently available options? The
evidence demonstrates that properly selected patients with metastatic kidney
cancer treated with IL-2 can be cured of their disease. Administration of high-dose IL-2 requires
admission to hospital for one week at a time with close monitoring by a
dedicated team. During the course of
treatment patients can have a flu-like syndrome and experience substantial
grade 3-4 toxicity secondary to capillary leak syndrome manifesting as
hypotension, oliguria, generalized edema, tachy-arrhythmias and hypoxemia. These toxicities, however, occur in a
monitored setting and are readily reversible.
As experience with high-dose IL-2 and management of its toxicities has
matured, the incidence of treatment-related irreversible high-grade toxicity
including death has been minimized, as evidenced by data being collected from
experienced centers in the PROCLAIM registry.
Mortality rates in experienced centers are less than 1%. While the oral route of administration,
non-life-threatening toxicities and broader applicability to most patients
makes targeted therapies extremely desirable, daily dosing with ongoing side
effects can significantly impact quality of life that needs to be balanced
against the unlikely chance of a durable response. Additionally the side effects that may
include diarrhea, stomatitis, fatigue, cardiac toxicity, increased incidence of
hemorrhagic and embolic phenomena, hand-foot skin syndrome, elevated
triglyceride levels, hyperglycemia and noninfectious pneumonitis occur in the
non-monitored environment. Appropriate
intervention for control of these symptoms is, therefore, largely dependent on
patient reporting and outpatient office response mechanisms.
Emerging data for new immunotherapeutic modalities is extremely exciting
and holds the promise of durable responses using agents administered in an
outpatient setting, safely offered to a broad patient population. Given the established durability of responses
with high-dose IL-2 and the ability to administer it safely at centers with
experience, our institutional approach, supported by the NCCN guidelines (42),
currently includes high-dose IL-2 as first-line, potentially curative therapy.
Acknowledgements: None
Conflict of Interest: None
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