Barbara J. Gitlitz

Treatment of Metastatic Renal Cell Carcinoma With Nephrectomy, Interleukin-2 and Cytokine-Primed or CD8(+) Selected Tumor Infiltrating Lymphocytes from Primary Tumor

PURPOSEnMetastatic renal cell carcinoma is a disease with a mean survival of 6 to 10 months. Interleukin-2 (IL-2), the only approved therapy for metastatic renal cell carcinoma, is associated with a 14% response rate and durable remissions in some patients with high performance status. We performed a series of trials of IL-2 plus tumor infiltrating lymphocyte cell therapy and report the clinical results from 62 patients enrolled in these trials.nnnMATERIALS AND METHODSnPatients were eligible if they had metastatic renal cell carcinoma with the primary tumor in place and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were treated with cytokines before nephrectomy and preparation of cytokine primed tumor infiltrating lymphocytes or CD8(+) tumor infiltrating lymphocytes were isolated for infusion into patients. Of 62 patients enrolled 55 were treated with tumor infiltrating lymphocytes and IL-2, and were evaluable for toxicity, response and survival.nnnRESULTSnThere were no postoperative mortalities. Of the patients 7 (11%) could not undergo systemic therapy. No unexpected IL-2 related toxicities or significant toxicities related to cell infusion were noted. Overall 5 patients (9.1%) achieved a complete response and 14 (25.5%) achieved a partial response. The responses were durable with a median duration of 14 months (range 0.8+ to 64+). The actuarial survival was 65% at 1 year and 43% at 2 years from the time of nephrectomy, with an overall median survival for all patients of 22 months (range 2 to 70+). The median survival for the responding patients has not yet been reached (range 2 to 63+).nnnCONCLUSIONSnThese results demonstrate that immunotherapy with radical nephrectomy, tumor infiltrating lymphocytes, and IL-2 provides substantial clinical benefit in the majority of patients. Component cellular therapy with enriched cell fractions allows the administration of a more standardized cell product. The present results with nephrectomy, tumor infiltrating lymphocytes and IL-2 are encouraging, and a randomized clinical trial of nephrectomy, CD8(+) tumor infiltrating lymphocytes, plus IL-2 versus nephrectomy and IL-2 alone is currently in progress.

REEVALUATION OF THE 1997 TNM CLASSIFICATION FOR RENAL CELL CARCINOMA: T1 AND T2 CUTOFF POINT AT 4.5 RATHER THAN 7 CM. BETTER CORRELATES WITH CLINICAL OUTCOME

PURPOSEnWe analyzed the effects of the change in TNM classification from the 1987 to the 1997 version and suggest a modified tumor size cutoff point between T stages 1 and 2 for renal cell carcinoma.nnnMATERIALS AND METHODSnWe evaluated a database containing the records of 661 patients who underwent nephrectomy between 1989 and 1999. The effect of the change in TNM classification on the distribution of patients between stages, the rates of M+ and N+ disease, and the local and distant recurrence rates were outlined for 280 patients with T stages 1 and 2 disease. The Cox model was used to identify the optimal cutoff point between T1 and T2 disease, and the resulting effect of adopting this cutoff was outlined.nnnRESULTSnA total of 174 and 128 cases were down staged from 1987 version stage T2 to 1997 version stage T1 and from 1987 TNM stage II to 1997 TNM stage I, respectively. Survival was not significantly different in patients with 1997 TNM stages I and II disease due to a lack of survival difference during the first 2 years of followup. Stage shift also caused an increase in average tumor size, the proportion of patients with high grade cancer, and M+ and N+ disease at diagnosis in 1997 stages T1 and T2 as well as an increase in the proportion of 1997 stage T2N0M0 cases at diagnosis with systemic failure. Analysis of 11 potential cutoff points between 1 and 10 cm. revealed that 4.5 cm. was most predictive of patients survival (hazards ratio 4.99, p = 0.0001). Using this cutoff resulted in improved discriminatory power of the TNM classification and a moderating effect on the distribution of patients, average tumor size, high grade disease, M+ and N+ disease at diagnosis, and systemic failure between T(14.5) and T(24.5) compared with 1997 T1 and T2.nnnCONCLUSIONSnOur data imply that the current cutoff point of 7 cm. between stages T1 and T2 tumors is too high. Lowering the cutoff to 4.5 cm. resulted in better discriminatory power of the TNM classification in our dataset. This observation should be further validated by external data.

COLLECTING DUCT RENAL CELL CARCINOMA: CLINICAL STUDY OF A RARE TUMOR

PURPOSEnCollecting duct carcinoma is a rare type of renal cell carcinoma that affects younger patients, and is associated with aggressive regional and distant spread. The clinical and pathological features of 6 patients with collecting duct carcinoma treated at a single institution are described.nnnMATERIALS AND METHODSnThere were 6 patients with collecting duct carcinoma included in the University of California School of Medicine, Los Angeles, Kidney Cancer Database. Demographic, clinical, pathological and survival data were gathered.nnnRESULTSnAverage patient age plus or minus standard deviation was 56 +/- 11 years, and 5 of 6 had TNM stage IV disease. The average survival of these patients was 11.5 months (range 7 to 17). There was 1 patient who had TNM stage I disease and survived without evidence of disease at 5 years. Transient response to chemotherapy was seen in 1 patient.nnnCONCLUSIONSnCollecting duct carcinoma is associated with poor prognosis. For the majority of patients surgical treatment will not result in a cure. Previously recommended chemotherapy and/or immunotherapy appears to have a limited role in treatment of this disease, and early detection may be the best method for prolonging patient survival.

Number of metastatic sites rather than location dictates overall survival of patients with node-negative metastatic renal cell carcinoma

OBJECTIVESnTo perform a retrospective study to determine whether survival and immunotherapy response are related to the site of metastases (lung versus bone) and to the number of organ sites involved (one versus multiple). The most common sites of metastatic renal cell carcinoma (mRCC) are the lung and bone.nnnMETHODSnThe records of 434 patients with mRCC were reviewed. Patients with pathologic evidence of nodal involvement were excluded, leaving 120 patients with mRCC to lung only, 33 patients to bone only, and 144 patients with multiple organ involvement. The response rates to immunotherapy and overall survival were compared. The variables evaluated in statistical analyses included Eastern Cooperative Oncology Group score, grade, 1997 tumor stage, and multiple organ involvement.nnnRESULTSnThe median survival for patients with lung only and bone only mRCC was 27 months; patients with multiple organ involvement had a median survival of 11 months. In patients who underwent nephrectomy followed by immunotherapy, the median survival time was 31, 31, and 13 months in the lung, bone, and multiple sites groups, respectively. The response rate to immunotherapy after nephrectomy was 44%, 20%, and 14% in the lung, bone, and multiple organ groups, respectively. Multivariate analysis confirmed that metastatic disease to more than one organ site was associated with poor prognosis (2.05 risk ratio, P <0.001).nnnCONCLUSIONSnPatients with mRCC to only one organ site fared significantly better than patients who had evidence of disease in multiple organs. Survival in patients with disease limited to the lung was similar to that of patients whose disease was limited to bone.

A phase II study of gemcitabine and docetaxel therapy in patients with advanced urothelial carcinoma.

The objectives of the current study were to evaluate the safety and efficacy of gemcitabine plus docetaxel in patients with unresectable (Stage T4 or ≥ N1) metastatic or locally advanced transitional cell carcinoma (TCC) of the urothelial tract.

Cytokine-based therapy for metastatic renal cell cancer

The use of recombinant gene technology to produce commercially available amounts of cytokines heralded an era of clinical applications of immunotherapy. Although the response rates to cytokine therapies are modest and sometimes occur at the expense of great cost and toxicity, they are proof of the principal that even large tumor burdens can be overcome by purely immune modulation. The interleukins and the interferons have been used in various phases of clinical trials in RCC. The maturation and final results of phase III trials are needed to guide clinical practice. In the meantime, the knowledge gained clinically and in the laboratory should lead to continued improvements and outcomes in immunotherapy for RCC.

Granulocyte/macrophage‐colony stimulating factor and interleukin‐4 expand and activate type‐1 dendritic cells (DC1) when administered in vivo to cancer patients

Two rare populations of cells with the features of dendritic cell precursors (preDC) can be identified in human peripheral blood. PreDC1 are HLA‐DR+/CD11c+ cells which mature into DC1 capable of stimulating Th1 responses. In contrast, preDC2 are HLA‐DR+/CD11c−/CD123+ cells that promote Th2 responses when matured into DC2. We hypothesized that administration of GM‐CSF and IL‐4, growth factors for DC1, would specifically augment the number and function of circulating DC1 in vivo. Patients with advanced metastatic cancer were treated with GM‐CSF (2.5 μg/kg/day) and IL‐4 (4 or 6 μg/kg/day) for 7 days. Cytokine administration at the highest IL‐4 dose produced an average 2.3‐fold increase in preDC2 number, but a 6.5‐fold increase in preDC1, resulting in an increased ratio of circulating preDC1:preDC2 from 1.4:1 pre‐treatment to 4.3:1 after cytokine therapy. DC1 precursors identified after in vivo therapy were larger, more complex and expressed higher levels of HLA‐DR, CD11c and CD80 than pre‐treatment cells. DC1 isolated from the peripheral blood of patients receiving GM‐CSF/IL‐4 therapy demonstrated MLR activity comparable to that of monocyte‐derived DC generated in vitro from the patients pre‐treatment blood using GM‐CSF and IL‐4. We conclude that systemic administration of GM‐CSF and IL‐4 preferentially expands and matures the preDC1 population in vivo. These effects correlate with antigen‐presenting activity, providing a mechanism by which systemic GM‐CSF and IL‐4 might stimulate anti‐tumor immunity in vivo.

Phase I trial of granulocyte macrophage-colony stimulating factor and interleukin-4 as a combined immunotherapy for patients with cancer.

Antigen-presenting cells (APC), such as dendritic cells (DC), are the key component of many cancer immunotherapy strategies. However, DCs comprise a rare population of clinically obtainable cells and are compromised in function in cancer-bearing hosts. Clinical trials therefore rely upon DC generated ex vivo. The authors hypothesized that systemic administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) plus interleukin (IL)-4 might lead to the differentiation of DC from their precursors and enhance their number and function in vivo, as it does in vitro. Subjects with advanced malignancies were treated in this phase I, multiple cohort, dose-escalation trial combining GM-CSF (2.5 &mgr;g/kg/d) plus IL-4 (0–6.0 &mgr;g/kg/d). A cycle consisted of 14 days of cytokine therapy and 14 days of observation (cohorts A–D), or alternating 7-day treatment and observation periods (cohort E). Subjects were followed clinically to determine a maximally tolerated dose (MTD), and complimentary in vitro studies were performed to determine a biologically active dose (BAD). Twenty-one subjects received treatment on this outpatient-based protocol. Treatment was well tolerated and generally characterized by Grade 1 and 2 cytokine related toxicities. The MTD was determined to be GM-CSF 2.5 &mgr;g/kg/d plus IL-4 6.0 &mgr;g/kg/d (cohort E). Treatment in cohort D (GM-CSF 2.5 &mgr;g/kg/d plus IL-4 4.0 &mgr;g/kg/d) was well tolerated and resulted in a BAD. Systemic GM-CSF plus IL-4 provides a mechanism for increasing the number and function of APC in cancer patients. Future clinical applications of this strategy are numerous and include the potential as a strong vaccine adjuvant.

Cell, gene and vaccine based strategies in kidney cancer.

T lymphocytes are the effector cells of the cellular immune system and recognize antigen via the T cell receptor (TCR), CD3 complex. There are 2 major T cell subsets based upon TCR-restricted recognition of major histocompatability complex (MHC) associated antigens. Antigen presenting cells (APC) such as dendritic cells (DC), macrophages, and tumor cells, continuously process and present both foreign and self antigens in association with MHC molecules. The TCR binds to the antigenic peptide sequence located in a grove formed by the MHC molecule.’ In general, CD8+ T-cells recognize antigen in association with class I MHC molecules and CD4+ T cells recognize antigen in association with class II MHC molecules. The binding of the TCR/CD3 complex to the MHC-antigen complex is crucial to the generation of effector cell function, including target cell lysis, T-cell clonal expansion, and secretion of cytokines.

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.