Overall survival with adjuvant atezolizumab after chemotherapy in resected stage II-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase III trial.

BACKGROUND: IMpower010 (NCT02486718) demonstrated significantly improved disease-free survival (DFS) with adjuvant atezolizumab versus best supportive care (BSC) following platinum-based chemotherapy in the programmed death-ligand 1 (PD-L1)-positive and all stage II-IIIA non-small-cell lung cancer (NSCLC) populations, at the DFS interim analysis. Results of the first interim analysis of overall survival (OS) are reported here. PATIENT AND METHODS: The design, participants, and primary-endpoint DFS outcomes have been reported for this phase III, open-label, 1 : 1 randomised study of atezolizumab (1200 mg q3w; 16 cycles) versus BSC after adjuvant platinum-based chemotherapy (1-4 cycles) in adults with completely resected stage IB (≥4 cm)-IIIA NSCLC (per the Union Internationale Contre le Cancer and American Joint Committee on Cancer staging system, 7th edition). Key secondary endpoints included OS in the stage IB-IIIA intent-to-treat (ITT) population and safety in randomised treated patients. The first pre-specified interim analysis of OS was conducted after 251 deaths in the ITT population. Exploratory analyses included OS by baseline PD-L1 expression level (SP263 assay). RESULTS: At a median of 45.3 months' follow-up on 18 April 2022, 127 of 507 patients (25%) in the atezolizumab arm and 124 of 498 (24.9%) in the BSC arm had died. The median OS in the ITT population was not estimable; the stratified hazard ratio (HR) was 0.995 [95% confidence interval (CI) 0.78-1.28]. The stratified OS HRs (95% CI) were 0.95 (0.74-1.24) in the stage II-IIIA (n = 882), 0.71 (0.49-1.03) in the stage II-IIIA PD-L1 tumour cell (TC) ≥1% (n = 476), and 0.43 (95% CI 0.24-0.78) in the stage II-IIIA PD-L1 TC ≥50% (n = 229) populations. Atezolizumab-related adverse event incidences remained unchanged since the previous analysis [grade 3/4 in 53 (10.7%) and grade 5 in 4 (0.8%) of 495 patients, respectively]. CONCLUSIONS: Although OS remains immature for the ITT population, these data indicate a positive trend favouring atezolizumab in PD-L1 subgroup analyses, primarily driven by the PD-L1 TC ≥50% stage II-IIIA subgroup. No new safety signals were observed after 13 months' additional follow-up. Together, these findings support the positive benefit-risk profile of adjuvant atezolizumab in this setting.

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.

PURPOSE: We 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. MATERIALS AND METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Our 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.

Vaccine and gene therapy of renal cell carcinoma.

The concept of tumor vaccines is not new. However, advances in gene transfer technology, tumor immunology, molecular biology, and methods of monitoring antitumor response, have allowed for novel, more specific vaccine approaches. For example, first-generation tumor vaccines were composed of whole inactivated cancer cells, or tumor lysates (Tuly) given together with immune adjuvants like bacillus Calmette-Guerin (BCG). Current strategies include tumor cells modified with genes encoding molecules necessary to stimulate a cytotoxic T cell response, such as cytokine genes, foreign HLA genes, tumor-associated antigen (TAA) genes, and even costimulatory molecules. Activation of cellular immunity requires at least three synergistic signals including presentation of specific tumor antigens, costimulatory signals (B7 molecules), and propagation of the immune response via cytokine release. In general, tumor cells often fail to demonstrate any of these immunostimulatory properties. Dendritic cell-based vaccines are gaining popularity as these cells can properly present TAA to the immune system, thus circumventing the poor antigen-presenting qualities of tumor cells. Dendritic cells can be "loaded" with TAA or other molecules either by their natural endocytotic capabilities, or by genetic modification.

Treatment of metastatic renal cell carcinoma with high-dose bolus interleukin-2 in a non-intensive care unit: an analysis of 124 consecutively treated patients.

PURPOSE: In prior studies of high-dose interleukin-2 (IL-2) therapy in the treatment of metastatic renal cell carcinoma, the majority of patients were asymptomatic (65% of patients had Eastern Cooperative Oncology Group [ECOG] scores of 0 [no cancer-related symptoms]). These studies demonstrated that an ECOG score of 0 predicted an objective antitumor response to IL-2 (P = 0.03). The current study determined the response frequency to high-dose IL-2 therapy in a primarily symptomatic patient population (ECOG = 1 [presence of cancer-related symptoms] for 57.3% of patients). The IL-2 therapy was administered in a non-intensive care unit (non-ICU). PATIENTS AND METHODS: In this single-institution study of high-dose IL-2 therapy, 124 patients were consecutively enrolled and treated with the drug. Antitumor responses and safety were assessed by radiographic methods and the occurrence of grade 3 and 4 adverse events, respectively. RESULTS: The frequency of objective responses was 14.5% (18 of 124 patients). Seven patients (5.6%) and 11 patients (8.9%) experienced complete responses (CRs) and partial responses (PRs), respectively. Two of 7 patients (28.6%) with CR and 7 of 11 patients (63.6%) with PR had ECOG scores of 1. The median response duration is 18 months for all responders (CR plus PR). The median survival duration is 15 months for all patients. It was not possible to estimate the median survival duration for all responders because the majority of responding patients were alive at close of study. All patients with CR and 5 patients with PR were alive at close of study. The frequency of grade 3 and 4 adverse events was comparable to or less than published data and IL-2 was safely administered in a non-intensive care unit. CONCLUSION: The frequency of objective antitumor responses in patients with ECOG scores of 1 suggests that high-dose IL-2 therapy may have comparable effectiveness in symptomatic and asymptomatic patients. High-dose IL-2 can be administered in a non-ICU setting with acceptable toxicity and the chance of clinical benefit.

Improved prognostication of renal cell carcinoma using an integrated staging system.

PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categorized was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival. RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman's grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis. CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients' survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.

Dendritic cell-based immunotherapy of renal cell carcinoma.

Although mostly resistant to cytotoxic therapy, renal cell carcinoma has been a testing ground for immunotherapy. The approval of interleukin-2 for the treatment of renal cell carcinoma was a landmark "proof of principle" which showed that agents working solely via the immune system can cause durable cancer remission. Dendritic cells are central to immune-mediated surveillance and destruction of abnormal cells. They possess all the components required to educate immune effector cells that can then mediate tumor destruction. In vitro strategies to expand and load dendritic cells with antigens have now led to human vaccine trials in renal cell carcinoma and other malignancies.

Adoptive cellular therapy.

We provide a current review of adoptive cellular therapy in the management of metastatic renal cell carcinoma. A comprehensive literature review of peer-reviewed articles on the development and use of adoptive cellular immunotherapy was performed. Renal cell carcinoma is a highly immunogenic tumor that has proven resistant to standard cytotoxic chemotherapy, but has shown reproducible response to immune-based therapy. In an effort to improve responses, a variety of adoptive cellular strategies have been devised and tested in the setting of metastatic disease. Among the techniques developed, the use of lymphokine-activated killer (LAK) cells, autolymphocyte therapy (ALT), and tumor-infiltrating lymphocytes (TIL) have been the best studied. While further trials are ongoing, thus far, these approaches have not consistently shown benefit in comparison to standard immune-based treatment with biologic response modifiers, most importantly, high-dose bolus interleukin-2 (IL-2). Future approaches, including the use of dendritic cells (DC) to facilitate the development of tumor vaccines, are encouraging. Advanced renal cell carcinoma continues to inspire research of promising new cellular immunotherapeutics. The experience with LAK, ALT, and TIL has greatly increased our understanding of tumor immunobiology, and has led to the ongoing development of new technology, including DC, vaccine, and antibody therapy.

Granulocyte macrophage colony-stimulating factor and interleukin 4 enhance the number and antigen-presenting activity of circulating CD14+ and CD83+ cells in cancer patients.

Antigen-presenting cells (APCs) are essential for stimulating antigen-specific immunity, including immunity against tumor cells. We hypothesized that systemic administration of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4, which promote monocytes to differentiate into dendritic cells in vitro, might enhance the number and antigen-presenting activity of CD14+ cells in vivo. Patients with metastatic solid malignancies were treated with daily s.c. injections of either GM-CSF alone (2.5 microg/kg/day) or GM-CSF in combination with IL-4 (0.5-6.0 microg/kg/day) in a multicohort study. When given alone, GM-CSF increased the number of CD14+ cells but did not enhance the cells' expression of APC markers or antigen-presenting activity. In contrast, combination therapy with GM-CSF and IL-4 stimulated CD14+ cells to acquire several APC characteristics including increased expression of HLA-DR and CD11c, decreased CD14, increased endocytotic activity, and the ability to stimulate T cells in a mixed leukocyte reaction. Combination therapy also induced a dose-dependent increase in the number of CD14-/CD83+ cells with APC activity. Clinically significant and sustained tumor regression was observed in one patient. Systemic therapy with GM-CSF and IL-4 may provide a mechanism for increasing the number and function of APCs in patients with cancer.

Immunomodulatory dendritic cells generated from nonfractionated bulk peripheral blood mononuclear cell cultures induce growth of cytotoxic T cells against renal cell carcinoma.

Dendritic cells (DCs) loaded with tumor antigens have the potential to become a powerful tool for clinical cancer treatment. Recently, the authors showed that a tumor-specific immune response can be elicited in culture via stimulation with autologous renal tumor lysate (Tuly)-loaded DCs that were generated from cytokine-cultured adherent peripheral blood mononuclear cells (PBMCs). Here, the authors show that immunomodulatory DCs can be generated directly from nonfractionated bulk PBMC cultures. Kinetic studies of DC differentiation and maturation in PBMC cultures were performed by monitoring the acquisition of DC-associated molecules using fluorescence-activated cell sorting analysis to determine the percentage of positive immunostained cells and the mean relative linear fluorescence intensity (MRLFI). Compared with conventional adherent CD14+ cultures, which have mostly natural killer, T, and B cells removed before cytokine culture, bulk PBMC cultures exhibited an early loss of CD14+ cells (day 0 = 78.8%, day 2 = 29.6% versus day 0 = 74%, day 2 = 75%) with an increase in yield of mature DCs (DC19- CD83+) (day 5 = 17%, day 6 = 21%, day 7 = 22% versus day 5 = 11%, day 6 = 15%, day 7 = 23%). Although a comparable percentage of DCs expressing CD86+ (B7-2), CD40+, and HLA-DR+ were detected in both cultures, higher expression levels were detected in DCs derived from bulk culture (CD86 = MRLFI 3665.1 versus 2662.1 on day 6; CD40 = MRLFI 1786 versus 681.2 on day 6; HLA-DR = MRLFI 6018.2 versus 3444.9 on day 2). Cytokines involved in DC maturation were determined by polymerase chain reaction demonstrating interleukin-6 (IL-6), IL-12, interferon-gamma, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-alpha mRNA expression by bulk culture cells during the entire 9-day culture period. This same cytokine mRNA profile was not found in the conventional adherent DC culture. Autologous renal Tuly (30 micrograms protein/10(7) PBMCs) enhanced human leukocyte antigen expression by DCs (class I = 7367.6 versus 4085.4 MRFLI; class II = 8277.2 versus 6175.7 MRFLI) and upregulated cytokine mRNAs levels. Concurrently, CD3+ CD56-, CD3+ CD25+, and CD3+ TCR+ cell populations increased and cytotoxicity against autologous renal cell carcinoma tumor target was induced. Specific cytotoxicity was augmented when cultures were boosted continuously with IL-2 (20 U/mL biological response modifier program) plus Tuly stimulation. These results suggest that nonadherent PBMCs may participate in enhancing DC maturation. Besides the simplicity of this culture technique, bulk DC cultures potentially may be used with the same efficiency as conventional purified DCs. Furthermore, bulk culture-derived DCs may be used directly in vivo as a tumor vaccine, or for further ex vivo expansion of co-cultured cytotoxic T cells to be used for adoptive immunotherapy.

Immunotherapy and gene therapy.

Currently, there are many options for the treatment of metastatic renal cell carcinoma (RCC). Being a mostly chemoresistant malignancy, renal cell carcinoma is usually treated with immunotherapy. These therapies are generally based on interleukin-2 (IL-2) or interferon alfa (IFN-alpha), or involve more novel techniques such as gene therapy. IL-2 is a biological agent that has been approved by the U.S. Food and Drug Administration and leads to durable remissions in a subset of patients with metastatic RCC. Patients presenting with a good performance status and without serious concomitant cardiac or pulmonary disorders should be considered for IL-2-based therapy as first-line treatment.