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The Use Of Interleukins For Advanced Melanoma

S.J. Miller, MD
Melanoma and Cutaneous Oncology Group, Johns Hopkins Hospital, Baltimore, Maryland, USA

ABSTRACT

Treatment of metastatic melanoma using traditional chemotherapy regimens has been disappointing. However, recent work with agents that modify the host’s immune system (e.g., interleukins) have provided limited but encouraging results. Interleukins are a group of molecules involved in immune cell signaling. As a high-dose, single agent therapy, Interleukin- 2 (IL-2) has produced durable, complete responses in a small, but real percentage of metastatic melanoma patients, but toxicities are significant and specialized care is required. The use of IL-2 in conjunction with other chemotherapeutic and biologic agents has produced an even higher percentage of complete responses, but the trials have been relatively small to date and durability is not as well proven. IL-2 is also being tested in conjunction with vaccines, activated immune cells, and other biologic response modifiers (including IL-12). It is hoped that these will lead to further increases in the number of metastatic melanoma patients who respond in a clinically meaningful fashion.

Key Words: metastatic melanoma, biochemotherapy, Interleukin-2, biologic response modifiers

Historically, metastatic melanoma has had a dismal prognosis, but recent use of biologic response modifiers, e.g., interleukins, to treat this disease has shown promise. The interleukins are a group of molecules involved in the growth, development and maintenance of a number of immune system cells and responses. The most widely studied interleukin in the treatment of metastatic melanoma is Interleukin-2 (IL-2).

IL-2, a 15kD glycoprotein, is produced and secreted by Tlymphocytes to activate and stimulate T-lymphocyte growth.1 Its effects in melanoma patients appear to be exclusively immunemediated, as no direct cytotoxic effects on melanoma cells are noted, even at high doses in cell culture.2 Current and future therapies involving IL-2 for patients with metastatic melanoma include:

  1. high-dose single agent IL-2 therapy
  2. multi-agent combined immunotherapy and chemotherapy (socalled “biochemotherapy”)
  3. IL-2 combined with other immune-modifying agents, including vaccines, activated immune cells, and other biologic response modifiers.

Single Agent IL-2 Therapy

Initial work with high-dose single agent IL-2 therapy in patients with metastatic melanoma was pioneered by Rosenberg.2 Additional work by Atkins and others followed,3,4 and results from 270 patients with 5-13 years of follow-up are now available.3 IL-2 was administered intravenously at 600,000 or 720,000 IU/kg every 8 hours for up to 14 consecutive doses over 5 days, as tolerated, with a second identical cycle one week later. Additional courses of therapy were then given every 6-12 weeks to stable or responding patients. Toxicities were frequently severe enough to require admission to an intensive care unit, and included hypotension, the so-called “vascular leak syndrome”, renal insufficiency, fever, nausea, vomiting, infection, and hepatic dysfunction.1 While much has been learned in recent years regarding toxicity and patient selection, high-dose IL-2 therapy still requires management by clinicians experienced in its use. In the above-noted meta-analysis, complete responses were observed in 6% of patients, many of whom have remained durable for years. These results suggest the possibility of a “cure” in a small percentage of patients treated with high-dose IL-2 therapy,4 and must be compared to older (e.g., single-agent chemotherapy) regimens, in which 5-year survival is on the order of 1-2%.3

Biochemotherapy

Biochemotherapy involves the sequential or concurrent infusion of multiple chemotherapeutic agents in conjunction with alphainterferon and IL-2. Some of the most impressive results with this therapy have come from Legha, et al. In a review of 114 metastatic melanoma patients treated with biochemotherapy, 10% of patients achieved complete remissions of at least 4 years duration.5 Toxicities can be significant, and include bone marrow suppression, infection, hypotension, constitutional toxicities, and the IL-2-related capillary leak syndrome. These side effects can be managed by experienced clinicians, and admission to an intensive care unit is rarely required. In a typical biochemotherapy regimen, IL-2 doses are moderate (9 x106 IU/m2/day by continuous IV) compared to the single agent high-dose IL-2 regimens. Some biochemotherapy regimens are even being tested using lower IL-2 doses, making them potentially suitable for an outpatient setting.6 However, low-dose single agent IL-2 has not shown clinical effectiveness in melanoma patients,4 and so its role in multi-agent therapy must be proven. While extremely promising, all investigations of biochemotherapy to date have involved single institution phase II trials, and follow-up is not as long as it was for the studies of single agent high-dose IL-2 therapy. The results of several prospective, randomized phase III trials7,8 of biochemotherapy regimens for patients with metastatic melanoma will mature in the next several years, and are awaited with interest.

Treatment Dosage Side Effects % of Complete Responses

High dose single agent IL-2 therapy

6 x 105 – 7.2 x 105 IU/kg q8hrs x 14 doses over 5 days. A second identical cycle is repeated 1 week later, and then every 6-12 weeks to stable or responding patients

Toxicity, e.g., hypotension, vascular leak syndrome, renal insufficiency, fever, nausea, vomiting, infection, hepatic dysfunction

6% of patients

Biochemotherapy (at phase III trial stage)

9 x 106 IU/m2/day by continuous IV

Toxicity, e.g., bone marrow suppression, infection, hypotension, constitutional toxicities, IL-2 related capillary leak syndrome

10% of patients

Vaccine (early stage trials)

Immunization using synthetic derivative of gp100 melanoma-associated antigen, then given high dose IL-2

No significant side effects reported

42% objective response

Dendritic cellular immune response vaccine (early stage trials)

Patient’s own dendritic cells grown in culture in presence of several melanoma-associated antigens, then injected back into patient in a series of vaccinations

No significant side effects reported

31% objective response

Table 1: Treatment options for metastatic melanoma.
Complete response = all measurable evidence of tumor disappeared for ≥ 1 month.
Partial response = all measurable evidence of tumor reduced by at least 50% for ≥ 1 month.
Objective response = the percentage of all partial and all complete responses in a population.

Future IL-2 Combinations

A number of trials were performed in the late 1980’s and early 1990’s using high dose IL-2 in conjunction with adoptive transfer of lymphokine-activated killer cells or tumor-infiltrating lymphocytes, but neither was shown to be more efficacious than high-dose IL-2 alone.9 However, the work with the tumorinfiltrating lymphocytes led to the discovery of many melanomarelated antigens, now in use in clinical trials involving vaccines. In one recent preliminary trial, 31 patients were immunized using a synthetic derivative of the gp100 melanoma-associated antigen and then given high-dose IL-2.10 Objective responses of 42% were seen, which is significantly higher than what is usually seen using high-dose single agent IL-2 therapy alone.

Dendritic cells are antigen-presenting cells that produce IL-12 and express IL-2 receptors on their cell surfaces. They promote the cellular immune response and maintain the viability of IL-2 activated T-lymphocytes.9 In one recent trial, melanoma patients’ dendritic cells were grown in cell culture in the presence of several melanoma-associated antigens, and then injected back into the patients in a series of vaccinations.11 Objective responses were noted in 31% of patients, and future trials in conjunction with IL-2 appear likely.

IL-12, like IL-2, is an interleukin with anti-cancer activity. It is secreted by antigen-presenting cells and activates cytotoxic lymphocytes.9 Several small trials of IL-12 in melanoma patients have been performed recently, including (a) the injection of genetically-engineered fibroblasts that constitutively produce IL- 12,9 and (b) the reintroduction of melanoma tumor cells into patients that have been transduced with the gene for IL-12 production.12 In both trials, clinical and immunological responses were noted. Animal studies have confirmed the synergistic antitumor activity of IL-2 and IL-12,13 and so human trials involving combinations of these interleukins appear likely.

Summary

Although the prognosis of metastatic melanoma remains grim, treatment with IL-2, either as a high-dose single agent or in conjunction with other chemotherapeutic agents and alphainterferon as biochemotherapy, appears capable of producing long-term complete remissions in a small percentage of patients. Current research protocols seek to further expand the immune response(s) of melanoma patients to their tumors, and will hopefully lead to an even greater number of patients who achieve meaningful clinical responses in their disease.

References

  1. Whittington R, Faulds D. Interleukin-2. A review of pharmacological properties and therapeutic use in patients with cancer. Drugs 46(3):446-514 (1993 Sep).
  2. Rosenberg SA. Interleukin-2 and the development of immunotherapy for the treatment of patients with cancer. Cancer J Sci Am 6(suppl 1):s2-7 (2000 Feb).
  3. Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6(suppl 1):s11-4 (2000 Feb).
  4. Atkins MB. Interleukin-2 in metastatic melanoma: what is the current role? Cancer J Sci Am 6(suppl 1):s8-10 (2000 Feb).
  5. Legha SS, Ring SR, Eton O, Bedikian A, Plager C, Papadopoulos N. Development and results of biochemotherapy in metastatic melanoma: the University of Texas M.D. Anderson Cancer Center experience. Cancer J Sci Am 3(Suppl 1):s9-15 (1997 Dec).
  6. Thompson JA, Gold PJ, Markowitz DR, Byrd DR, Lindgren CG, Fefer A. Updated analysis of an outpatient chemoimmunotherapy regimen for treating metastatic melanoma. Cancer J Sci Am 3(Suppl 1):s29-34 (1997 Dec).
  7. Thompson JA, Gold PJ, Markowitz DR, Byrd DR, Lindgren CG, Fefer A. Updated analysis of an outpatient chemoimmunotherapy regimen for treating metastatic melanoma. Cancer J Sci Am 3(Suppl 1):s29-34 (1997 Dec).
  8. Punt CJA, Gore M, Kruit W, et al. Dacarbazine, cisplatin and interferon alpha with or without interleukin-2 in advanced melanoma: interim analysis of EORTC trial 18951. ASCO Proc 18:530a (1999).
  9. Lotze MT, Hellerstedt B, Stolinski L, et al. The role of interleukin-2, interleukin-12, and dendritic cells in cancer therapy. Cancer J Sci Am 3(Suppl 1):s109-14 (1997 Dec).
  10. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 4(3):321-7 (1998 Mar).
  11. Nestle FO,Alijagic S, Gilliet M, et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 4(3):328-32 (1998 Mar).
  12. Sun Y, Jurgovsky K, Moller P, et al. Vaccination with IL-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study. Gene Ther 5(4):481-90 (1998 Apr).
  13. Lissoni P. Effects of low-dose recombinant interleukin-2 in human malignancies. Cancer J Sci Am 3(Suppl 1):s115-20 (1997 Dec).

In this issue:

  1. Topical Tacrolimus
  2. The Use Of Interleukins For Advanced Melanoma
  3. Update on Drugs and Drug News - Number 4 2000