Robert A. Figlin

Multicenter, Randomized, Phase III Trial of CD8+ Tumor-Infiltrating Lymphocytes in Combination With Recombinant Interleukin-2 in Metastatic Renal Cell Carcinoma

PURPOSEnTo prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients.nnnPATIENTS AND METHODSnBetween December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs.nnnRESULTSnOf 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board.nnnCONCLUSIONnTreatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

The Evolution of Systemic Therapy in Metastatic Renal Cell Carcinoma

The treatment landscape for renal cell carcinoma (RCC) is a dynamic process that has seen considerable change in recent years. We have seen a rebirth of original breakthroughs with immune checkpoint inhibitors showing promise in patients with treatment-refractory disease. The optimal sequencing of treatments and incorporation of novel therapeutics are actively being investigated and have yet to be determined. The clinical challenges of this evolving treatment paradigm can be attributed to cost considerations, toxicity, and defining endpoints in the management of advanced RCC. As novel therapeutics emerge, finding the optimal treatment regimen for patients will have an increasing focus on patient-centered outcomes and improvement in quality of life in addition to improving survival.

Renal Cancer Vaccines

It is estimated that approx 30,000 new cases of renal cell carcinoma (RCC) were diagnosed in 2002 (1). Approximately 20–30% of patients with RCC present with metastatic disease and their overall median survival is 6–8 mo (2). Although, metastatic RCC carries a poor prognosis, in a small subset of patients the disease has a variable course (3). Oliver et al. observed 73 patients with metastatic RCC without treatment (4). In this series, 4% had complete and spontaneous regression of disease and 3% had partial regression of disease. Furthermore, 5% had stable disease with no evidence of progression for more than 12 mo. There are also numerous cases of patients who recur with metastatic RCC over 10 yr after undergoing a nephrectomy for apparently localized disease. It is presumed from these observations that the immune system plays a key role in cases of spontaneous regression and durable remissions of RCC.

Adoptive Immunotherapy in Renal Cell Carcinoma

The study of cancer immunotherapy has gained increasing popularity since Dr. William Coleys’ observations in the late 19th century of patient tumor shrinkage after life-threatening bacterial infections. The idea that tumor cells, similar to invading foreign pathogens, can express abnormal antigens has formed the basis of attempts to manipulate the immune system to cause improved tumor surveillance and destruction. Over the last two decades, considerable strides have been made in the field of tumor immunology. This includes further knowledge of antigen processing and presentation via the major histocompatability complex (1, 2); understanding the interaction between T cells and antigen presenting cells (APC) via the T-cell receptor (TCR) (3), secondary signals such as costimulatory molecules, regulation of the immune response by cytokines, and most notably the characterization of a variety of genes-encoding tumor-associated antigens (TAA). For many tumor types, the DNA and amino acid sequences of TAA have been worked out including the immunodominant peptide restricted by major histocompatibility complex (MHC) rules. These relatively recent discoveries have allowed for the exploration of more targeted immunotherapies. The transfer of cells with antitumor reactivity is termed adoptive immunotherapy and shows promise in the treatment of selected malignancies. Adoptively transferred T cells have been shown to bring about regression in animal tumor models (4–6), and have been studied in human clinical trials since the 1980’s. It is now evident that the potential of adoptive therapy seen in animal models has not yet fully translated into human models. However, there are well-documented studies demonstrating durable responses in human cancers, most notably renal cell carcinoma (RCC) and melanoma. This chapter will focus on the development of adoptive immunotherapy for RCC, its shortcomings, and potential for improvement. Adoptive immunotherapy employing autolymphocyte therapy (ALT), lymphokine-activated killer cells (LAK), and tumor infiltrating lymphocytes (TIL) will be featured, as will other promising approaches.