Interleukin-2

Background:

Interleukin-2 (IL-2) was initially investigated by a number of labs as a T-cell growth factor and subsequently developed as a medical therapy for kidney cancer and melanoma in the early 1980s by Steven Rosenberg at the National Institutes of Health. It won Food and Drug Administration (FDA) approval in 1992 and has been marketed since then under the name Proleukin by the Chiron Corporation based in Emeryville, California. In 2006, Chiron merged with Novartis Pharmaceuticals. Novartis has subsequently sold the American distribution rights to Prometheus Labs.

Interleukin-2 is a cytokine, which is a protein that acts as a regulator of the body’s immune system, similar to interferon. By giving the patient large doses of this protein, it is hoped that the body’s own immune system will destroy the cancer cells. Interleukin-2 is administered via intravenous (IV) injection as high dose (HD) (usually defined as 600,000 – 720,000 units/kg). Lower dosage IV and subcutaneous IL-2 are also prescribed for kidney cancer, but HD IL-2 is the only regimen that has FDA approval. The other uses are off-label.

HD IL-2 is highly toxic, and although it is administered for a brief cycle, usually one week, it must be given in a hospital setting where the patient can be closely monitored by physicians and staff who have significant experience in its use. The prospective candidate must be in fairly good health to qualify for this drug. For example, he or she must have a creatinine level < 1.5, have no uncontrolled heart arrhythmia, and have good pulmonary and liver function.

Side Effects of HD IL-2:

The patient often experiences flu-like symptoms during treatment, i.e. chills, fever, malaise, nausea, and diarrhea. More of a problem can be hypotension and renal issues (renal toxicity, oliguria,[1] and increased creatinine). The side effects usually disappear shortly upon completion of treatment. For the management of side effects of HD IL-2 treatment, see Janice Dutcher’s article in the Kidney Cancer Journal .[2]

When HD IL-2 treatment was in its early days, there were treatment related mortalities. Since that time, practitioners have gained sufficient experience to improve the safety of the drug. The National Cancer Institute conducted a study[3] investigating the safety of HD IL-2 administered to metastatic patients (a total of 1241 renal cell carcinoma and melanoma patients) over a 12-year period. They found a “progressive reduction in morbidity and mortality” due to the ability to better screen patients, to control the therapeutic conditions, and to terminate dosing when faced with toxicities. At the same time, there was no significant reduction in complete response rates for renal cell and melanoma patients over this period.

Efficacy Studies:

Since Interleukin-2 was approved for use in kidney cancer by the FDA, several studies have been conducted to qualify its effectiveness including two seminal studies comparing high dose (HD) versus low dose (LD) IL-2.

David McDermott of the Beth Israel Deaconess Medical Center in Boston was the principal investigator[4] on a Cytokine Working Group[5] sponsored, randomized Phase III trial of 192 patients (165 of them clear cell) testing high-dose IL-2 (HD IL-2) versus a combination of subcutaneous IL-2 and Interferon-alpha (INF). The trial, which ran from April 1997 to July 2000, showed the following:

Summary of Tumor Response Data:

As can be seen, only HD IL-2 had a durable, 3-year complete response (CR) rate (7.4%) for metastatic RCC (mRCC). For HD IL-2 therapy, the overall response rate for patients with liver or bone metastases was comparable to that of patients with other metastatic sites. However, for the patients taking the combination of subcutaneous IL-2 and Interferon-alpha, the story was quite different.

The median response duration was 24 months for HD IL-2 therapy compared with 15 months for LD IL-2 and INF, but the difference was not statistically significant. The difference in the overall median survival, although favoring HD IL-2, 17.1 months to 13.0 months, was also not statistically significant.

Nevertheless, McDermott concluded that HD IL-2 offers a response and survival benefit over the combination of subcutaneous IL-2 and Interferon-alpha to mRCC patients, especially those with liver or bone metastases and that a medically qualified patient should be prescribed HD IL-2 in preference to the low dose combination. He further stated that given the toxicity of the drug, better patient selection criteria should be developed. The only advantage for subcutaneous IL-2/INF was in having fewer side effects.

James Yang of the National Institutes of Health ran an earlier 2-arm randomized study (1991-2001) of 400 clear cell patients randomized to either HD IL-2 or low dose (LD) IL-2 (by intravenous IV), with subsequent comparison to a 3-arm trial with the patients randomized to HD IL-2, LD IL-2, or subcutaneous IL-2[6]. The patients in the HD IL-2 and LD IL-2 arms of the 3-arm trial were a subset of those in the 2-arm trial. The results were as follows.

Patient Response:

Yang found no significant differences[7] in survival for HD and LD IL-2, but stated that without a large scale trial it would be difficult to differentiate survival benefit when the RESPONSE rate is below 10%. A better substitute for the efficacy of the drug would be response rates and duration of response.
  • HD IL-2: Of the 11 CR (7%), 8 of 11 were still disease-free at a median of 9.3 years. Two had minor recurrences that were resected and remain disease-free. One patient died.
  • LD IL-2 (IV): Of 6 CR (4%), 3 of 6 had durable CR after 10 years with 3 patients dying.
  • LD IL-2 (subcutaneous (sc)): Of 2 CR (2%), 1 was durable.

The survival of patients completely responding (CR) to HD IL-2 and LD IL-2 differs significantly. So if one were to attain a complete response from IL-2 treatment, the chances of survival are enhanced if the treatment was from HD IL-2 rather than LD IL-2.

Interestingly, a statistical analysis of the data from his trial “demonstrated stabilization of survival at approximately 4 years” for those patients who had a complete response to the drug. In other words, once a patient reached four years of survival, they did not regress. Although this conclusion was based on a small sample of 11 cases, this has also been the anecdotal experience of over 20 years among the experienced physicians in the Cytokine Working Group and others who use IL-2.

Yang postulated that the efficacy of the drug may be separated from its toxicity. But he recommended that the dosage not be decreased to reduce toxicity, since the drug’s effectiveness will also be reduced and that toxicities are reversible when administration of the drug ceases. However, he does recommend LD IL-2 where the patient cannot qualify medically for high-dose. Finally, Yang stated that “the value of IL-2 for patients with renal cell lives in the small probability that this drug can be curative for some patients with metastatic disease”.

Response to IL-2 and Histology:

In a retrospective study[8], Melissa Upton reported that patients who had clear cell carcinoma with alveolar[9] features, no papillary features, and granular features < 50% had a response rate of 25% compared to 4% for the rest of the population. She concluded that patients with variant (non-clear cell) or indeterminate RCC or with clear cell with papillary and/or no alveolar features and/or > 50% granular features should not be candidates for IL-2 therapy.

A prospective trial called the “Select” trial opened in 2006, sponsored by the Cytokine Working Group, to test if the presence of the two markers, high expression of carbonic anhydrase IX (CAIX) and alveolar features, as well as other parameters, act as a predictor of successful immune response to HD IL-2 treatment.

The principal investigator of this multi-institution trial is David McDermott of Beth Israel Deaconess Medical Center in Boston.

Conclusions:

HD IL-2 remains a viable option for a selective group of patients with mRCC. It remains the only therapy that has demonstrated a durable, complete response in kidney cancer, albeit small. Since it is toxic it must be administered in a hospital by a physician highly experienced in its use[10].

The treatment phase for IL-2 is short and the side effects are temporary, which is in distinction to the newer targeted therapies, which must be taken continuously in order to remain effective. Finally, since only a minority of the population responds to IL-2, the results of the “Select” trial are eagerly anticipated to give the kidney cancer community the tools to choose appropriate candidates for future HD IL-2 therapy.


[1] Decreased production in urine[2] Is High-Dose Interleukin-2 the Treatment of Choice for Metastatic Renal Cell Carcinoma?, Janice Dutcher, Kidney Cancer Journal, 1: 5-12 2003[3] Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer, Kammula, White, Rosenberg, Cancer, 1998 Aug 15;83(4):797-805

[4] Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients with Metastatic Renal Cell Carcinoma, McDermott et al, Journal of Clinical Oncology 23: 133-141 2005

[5] The Cytokine Working Group (CWG) was established in 1986 with funding from the National Cancer Institute with the mandate to verify the efficacy of high-dose Interleukin-2 as a treatment for renal cell carcinoma. The CWG has conducted a number of clinical trials to determine the efficacy and safe dosage of IL-2.

[6] Randomized Study of High-Dose and Low-Dose Interleukin-2 in Patients with Metastatic Renal Cancer, Yang et al, Journal of Clinical Oncology 21: 3127-3132 2003

[7] Significant response is a statistical term and doesn’t imply that there was no actual difference in actual survival. For example, in the McDermott study, the median survival for high-dose IL-2 versus low-dose IL-2 and INF was 17 months versus 13 months, which obviously connotes a “trend in survival benefit favoring HD IL-2″ , but it is not statistically significant given the small difference between the two.

[8] Procedures of the American Society of Clinical Oncology 22:2003 abstract 3420

[9] Alveolar features refers to the fact that under microscopic examination the tumor tissue resembles the pattern of alveoli or air sacs in the lungs.

[10] Novartis, the manufacturer of Proleukin, their trade name for IL-2 therapy, has a website that lists Proleukin Treatment Centers, http://www.proleukin.com/info/treating/treatment-centers.jsp. At the time of our observation, October 2007, it was somewhat out-of-date and had inaccuracies, but Novartis promised to clean it up and to update it on a semi-annual basis.