Immunotherapy in Renal Cell Carcinoma
Immunotherapy in Renal Cell Carcinoma
ABSTRACT: Patients with metastatic renal cell carcinoma continue to present a therapeutic challenge. Current therapeutic approaches involve surgery and various types of immunotherapy. The rationale for this latter form of therapy include the observations of spontaneous tumor regression, the presence of a T-cell–mediated immune response, and the tumor responses observed in patients receiving cytokine therapy. Analysis of prognostic factors in these patients demonstrates that clinical responses occur most frequently in individuals with good performance status. The cytokines interleukin-2 (IL-2, aldesleukin [Proleukin], interferon-alfa (Intron A, Roferon-A) , or the combination produce responses in 15% to 20% of patients. Randomized trials suggest that administration of interferon-alfa may result in a modest improvement in median survival. Investigation of the molecular genetics of renal cell carcinoma and the presence of T-lymphocyte immune dysregulation have suggested new therapeutic strategies. Further preclinical and clinical studies investigating inhibitors of angiogenesis or pharmacologic methods to reverse immune dysregulation are ongoing. Therapeutic results in patients with renal cell carcinoma remain limited, and investigational approaches are warranted. [ONCOLOGY 13(6):801-810, 1999]
Renal cell carcinoma is an epithelial malignancy that appears to be slowly increasing in incidence. It is estimated that 30,600 new cases of kidney cancer are diagnosed annually in the United States, and 12,000 deaths result from this tumor each year. Since 1935, the rate of increase of renal cell carcinoma has slowed somewhat but approximates 2% per annum.
Histologically, renal cancer encompasses a heterogeneous group of diseases. The most common histologic type is clear cell cancer (Figure 1a), which accounts for approximately 75% of renal carcinomas. Papillary tumors (Figure 1b) occur in only 15% of patients, and other malignancies, such as sarcomatoid, collecting duct, and medullary tumors, develop in fewer than 5%.
Recent molecular genetic studies have identified mutations of the von Hippel Lindau (VHL) gene in patients with clear cell carcinoma. It appears that vascular endothelial growth factor (VEGF) may be under the regulation of the VHL protein product. Mutant forms of this protein, such as are found in clear cell cancer, may be associated with enhanced expression of VEGF. The vascular nature of renal tumors, together with these observations, suggest that methods to inhibit VEGF expression may be of therapeutic interest.
In addition, some renal tumors express c-met. This proto-oncogene codes for a protein that functions as a receptor for hepatocyte growth factor.
These kinds of studies have provided insights into the genetic defects occurring in renal cancer and may lead to new treatment approaches. Current therapeutic approaches in patients with advanced disease continue to involve surgery and various forms of immunotherapy, however.
Figure 2 shows the distribution by stage of patients with newly diagnosed renal cell carcinoma. Close to half of patients (45%) have localized disease at diagnosis. However, approximately 30% of individuals have metastatic disease, and another 25% have locally advanced tumors with lymph node and/or local organ involvement.
In patients with metastatic renal cell carcinoma, 3- to 5-year survival rates are less than 5%. Outcomes differ in subsets of individuals with advanced disease, however. In patients who have synchronous metastatic disease or who develop metastases within 12 months of surgery, the 2-year survival rate approaches 0%. In contrast, patients in whom metastatic disease develops more than 2 years from diagnosis have a 5-year survival rate of over 20%. In addition, various prognostic factors play an important role in determining therapeutic outcomes in patients with metastatic renal cancer. The most important factor identified to date is performance status.
Rationale for Use
The possibility that the immune response may control the progression of cancer was suggested over 40 years ago. In patients with renal cancer, three observations have provided a rationale for the use of immunotherapy.
Spontaneous Regression—The first observation, spontaneous regression, was recognized originally in patients in whom synchronous metastatic disease regressed after removal of the primary tumor. Recent reviews suggest that this phenomenon is very uncommon.
In addition, it has been observed that pulmonary metastases may undergo regression in a subset of patients with metastatic renal cancer. In two trials, one conducted by Oliver and colleagues and the second by the Canadian Urologic Group, approximately 5% to 7% of patients had transient partial regressions of pulmonary nodules that were unrelated to therapy.
T-Cell–Mediated Immune Responses—The second observation is the presence of a T-lymphocyte–mediated immune response in patients with renal cancer. Immunohistologic examination of renal tumors demonstrates infiltration by T-lymphocytes (Figure 3), as well as macrophages. In approximately 25% of patients, these tumor-infiltrating lymphocytes are cytolytic and/or produce cytokines in response to autologous tumor in a major histocompatibility complex (MHC)–restricted fashion. Recent studies have attempted to define the antigens recognized by these T-lymphocytes.
Clinical Responses to Biological Agents—The last observation is the occurrence of clinical responses in patients receiving biological agents, such as the cytokines. The cytokines used have included the interleukin and interferon families, as well as the colony-stimulating factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim- [Leukine, Prokine]), and macrophage colony-stimulating factor (M-CSF).
Of the interleukin family, recombinant human interleukin-2 (rHu-IL-2, aldesleukin [Proleukin]) is the predominant agent used in patients with renal cell carcinoma. This protein is a growth factor that enhances the proliferation and function of T-lymphocytes.
In view of the T-lymphocyte population found in renal tumors, this cytokine was studied in kidney cancer patients. A recent review of clinical results in over 1,700 patients (Table 1) suggests that regression rates in individuals receiving rHu-IL-2 are approximately 15% to 16%.
Three schedules have been used: a high-dose intravenous bolus approach, continuous IV infusion, and subcutaneous administration. In patients receiving high-dose intravenous rHu-IL-2, the complete regression rate was approximately 5%, whereas in those given the other regimens, this frequency tended to be somewhat lower (approximately 2% to 3%). In addition, the complete responses in patients receiving high-dose rHu-IL-2 appeared to be durable in many instances. Overall, however, clinical results did not appear to differ significantly with different methods or schedules of administering rHu-IL-2.
Randomized Trial—In order to compare these approaches, randomized clinical trials are necessary, since prognostic factors can significantly influence the outcome in renal cancer patients. A recent National Cancer Institute (NCI) randomized trial compared high-dose, intravenous-bolus rHu-IL-2 (720,000 IU/kg every 8 hours for 15 doses) with a lower-dose bolus (72,000 IU/kg every 8 hours for 15 doses) schedule in over 200 patients. The overall response rates were 19% and 10% in the high- and low-dose groups, respectively, with no differences in median response duration or median survival between the two groups. Currently, the NCI is conducting a second trial to compare high-dose intravenous rHu-IL-2, a low-dose intravenous regimen, and subcutaneous rHu-IL-2.
A second cytokine that is widely used for the treatment of renal cancer is interferon-alfa (Intron A, Roferon-A). This pleiotropic protein has antiviral, immunomodulatory, and antiproliferative activities.
A recent review of over 1,500 patients (Table 2) suggested that tumor regression occurs in 12% to 15% of patients following administration of interferon alfa. However, response rates may vary somewhat between the interferon preparations, ranging from 12% to 18%. Complete responses occur in 2% to 5% of patients and are generally seen in individuals with pulmonary metastases.
The optimal therapeutic dose of interferon is not well defined, but appears to be between 5 and 10 MU/m² administered as a subcutaneous injection 3 to 5 days weekly.
Randomized Trials—Unlike rHu-IL-2, randomized trials have been conducted in which interferon-alfa has been compared with other approaches. These include comparisons with non-cytokine–containing regimens and/or regimens containing other cytokines.
The studies of greatest interest (Table 3) are those reported in a preliminary fashion by Pyrhönen et al and Ritchie et al. Pyrhönen et al conducted a trial in approximately 160 patients with metastatic disease who received either interferon-alfa and vinblastine or vinblastine alone. This trial detected significant differences in response rates in patients treated with interferon-alfa plus vinblastine compared with vinblastine alone (16.5% vs 2.5%). Median survival durations also differed significantly between the two groups (15.8 vs 8.8 months). These results suggest that interferon as a single agent may enhance survival since the clinical activity of vinblastine is minimal.
Ritchie et al compared renal cancer patients receiving interferon-alfa (10 MU subcutaneously three times weekly) with those receiving methoxyprogesterone (300 mg/d). This study, which involved over 330 patients, was closed early because of differences in median, 1-, and 2-year survival rates. Clinical results in patients treated with interferon-alfa were significantly better than results in patients given methoxyprogesterone. In patients with measurable disease, interferon-alfa produced responses in 13% and methoxyprogesterone in 7%. This study concluded that interferon-alfa significantly enhances survival in patients with metastatic renal cell carcinoma.
A third trial that was somewhat smaller than the latter two studies did not demonstrate a significant improvement in survival but the trends were suggestive. Thus, the findings of these trials suggest that interferon-alfa may enhance survival in patients with metastatic renal cell cancer, although the effect appears to be modest.