T Cell–Based Immunotherapy of Metastatic Renal Cell Carcinoma: Modest Success and Future Perspective

Shablak, Alaaeldin; Hawkins, Robert E.; Rothwell, Dominic G.; Elkord, Eyad

doi:10.1158/1078-0432.ccr-09-1605

Cited by 33 publications

(32 citation statements)

References 99 publications

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“…Therefore, the induction of apoptosis is an important reason for depletion of the activated T cells in tumor microenvironment. For many years, different strategies for immunotherapy have been explored for tumor therapy, including the adoptive transfer of tumor-specific T cells that have been activated and expanded in vitro (45)(46)(47)(48). The presence of immune suppressor cells has become a substantial obstacle to the success of tumor immunotherapy.…”

Section: Il-10 Enhances the Apoptosis-inducing Capacity Ofmentioning

confidence: 99%

Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+F4/80+ Cells to Induce Apoptosis of Activated T Cells

Liu

Sun²,

Wei³

et al. 2010

The Journal of Immunology

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Gr-1+CD11b+F4/80+ cells play important roles in tumor development and have a negative effect on tumor immunotherapy. So far, the mechanisms underlying the regulation of their immunosuppressive phenotype by classical and alternative macrophage activation stimuli are not well elucidated. In this study, we found that molecules from necrotic tumor cells (NTC-Ms) stimulated Gr-1+CD11b+F4/80+ cells to induce apoptosis of activated T cells but not nonstimulated T cells. The apoptosis-inducing capacity was determined by higher expression levels of arginase I and IL-10 relative to those of NO synthase 2 and IL-12 in Gr-1+CD11b+F4/80+ cells, which were induced by NTC-Ms through TLR4 signaling. The apoptosis-inducing capacity of NTC-Ms–stimulated Gr-1+CD11b+F4/80+ cells could be enhanced by IL-10. IFN-γ may reduce the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells only if their response to IFN-γ was not attenuated. However, the potential of Gr-1+CD11b+F4/80+ cells to express IL-12 in response to IFN-γ could be attenuated by tumor, partially due to the existence of active STAT3 in Gr-1+CD11b+F4/80+ cells and NTC-Ms from tumor. In this situation, IFN-γ could not effectively reduce the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells. Tumor immunotherapy with 4-1BBL/soluble programmed death-1 may significantly reduce, but not abolish the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells in local microenvironment. Blockade of TLR4 signaling could further reduce the apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells and enhance the suppressive effect of 4-1BBL/soluble form of programmed death-1 on tumor growth. These findings indicate the relationship of distinct signaling pathways with apoptosis-inducing capacity of Gr-1+CD11b+F4/80+ cells and emphasize the importance of blocking TLR4 signaling to prevent the induction of T cell apoptosis by Gr-1+CD11b+F4/80+ cells.

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Section: Il-10 Enhances the Apoptosis-inducing Capacity Ofmentioning

confidence: 99%

Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+F4/80+ Cells to Induce Apoptosis of Activated T Cells

Liu

Sun²,

Wei³

et al. 2010

The Journal of Immunology

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“…In renal cell carcinoma (RCC), a similar breakthrough has not yet occurred (7), although clinical data, including spontaneous remissions and the response to cytokine therapy (8)(9)(10), suggest that these tumors are susceptible to immune-mediated effector mechanisms. Furthermore, T cells were found in the tumors and blood of patients who had reactivity against RCC lines when tested ex vivo (11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

mentioning

confidence: 99%

T-Cell Receptor Gene–Modified T Cells with Shared Renal Cell Carcinoma Specificity for Adoptive T-Cell Therapy

Leisegang

Turqueti-Neves

Engels

et al. 2010

Clinical Cancer Research

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Purpose: Adoptive therapy with genetically engineered T cells carrying redirected antigen specificity is a new option for the treatment of cancer. This approach is not yet available for metastatic renal cell carcinoma (RCC), due to the scarcity of therapeutically useful reagents. We analyzed tumor-infiltrating lymphocytes (TIL) from RCC to identify T-cell specificities with shared tumor-specific recognition to develop T-cell receptor (TCR)-engineered T lymphocytes for adoptive therapy of RCC.Experimental Design: We established a T-cell clone from TIL that recognized a human leukocyte antigen (HLA)-A2-restricted tumor antigen. The TCR α-and β-chain genes were isolated, modified by codon optimization and murinization, and retrovirally transduced into peripheral blood lymphocytes (PBL). A TCR-expressing indicator line (B3Z-TCR53) was established to screen for antigen prevalence in RCC, other malignancies, and normal cell counterparts.Results: TCR53-engineered PBL recapitulated the specificity of the TIL and showed tumor-specific HLA-A2-restricted effector activities (IFN-γ, tumor necrosis factor-α, interleukin-2, macrophage inflammatory protein-1β, cytotoxicity). PBL-TCR53 of healthy donors and RCC patients exhibited similar transduction efficiency, expansion, and polyfunctional profile. Using B3Z-TCR53 cells, 130 tumor and normal cells were screened and shared TCR53 peptide: MHC expression was found in >60% of RCC and 25% of tumor lines of other histology, whereas normal tissue cells were not recognized.Conclusions: To date, TCR53 is the only TCR with shared HLA-A2-restricted recognition of RCC. It fulfills the criteria for utilization in TCR gene therapy and advances T cell-based immunotherapy to patients with RCC and other malignancies expressing the TCR ligand.

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“…CD3+/CD56+ cells, which comprise a rare population of cells in normal peripheral blood, are also significantly increased after stimulation and expansion. These may be the most important cells for the anti-cancer effect of CIK treatment (36) as they have shown strong anti-cancer activity in a variety of malignant tumor cell lines in vitro (20,25,37). Therefore, we have good reason to hypothesize that our improved methods have allowed us to obtain R-CIK cells with particularly strong anti-tumor activity for transferring them to patients.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of RetroNectin-activated cytokine-induced killer cell therapy in the treatment of advanced hepatocelluar carcinoma

Wang

Kellner

et al. 2016

Oncology Letters

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Abstract. The present study aimed to investigate the efficacy of RetroNectin-activated cytokine-induced killer cell (R-CIK) therapy in advanced hepatocellular carcinoma patients as compared with conventional chemotherapy, a comparison that has not yet been thoroughly studied. From January 2010 to October 2013, 74 patients with an initial diagnosis of advanced hepatocelluar carcinoma were enrolled in the study. Patients were assigned to one of two treatment arms: patients in arm 1 (n=37) received R-CIK treatment as the first line therapy, whereas those in arm 2 (n=37) received chemotherapy as the first line treatment. The primary end point measured in this study was median overall survival (mOS). Median progression-free survival time (mPFS) and 1-and 2-year survival rates were recorded as secondary end points. Kaplan-Meier analysis was performed on all mOS and mPFS data, and treatment hazard ratios were established using the Cox proportional hazards model. The 1-year survival rate in treatment arm 1 was 42.47% vs. 24.89% in arm 2 (95% CI, 24.91-59.01% vs. 12.10-40.02%, P=0.066); the 2-year survival rates were 21.24 and 5.53% (95% CI, 4.60-45.86 vs. 0.46-21.06%, P= 0.106) in arms 1 and 2, respectively; the mPFS in arm 1 was 4.37 vs. 3.90 (x 2 = 0.182, P=0.670) in arm 2; and the mOS in arm 1 was 14.03 months vs. 9.46 months(x 2 =4.406, P=0.036) in arm 2. Calculations of univariate analyses of arm 1, R-CIK cycles ≥6, KPS >70, AFP ≤400 ng/ml, and findings of no vascular invasion and no extra-hepatic metastasis were potential predictive factors (P<0.05). Calculations from multivariate analyses similarly identified these factors as potentially having predictive value (P<0.05). The main adverse effects of R-CIK therapy included fever and headache pain. R-CIK treatment may prolong mOS in advanced hepatocellular carcinoma patients compared with conventional chemotherapy. Patients who underwent ≥6 cycles of R-CIK, had KPS scores >70, AFP ≤400 ng/ml, displayed no evidence of vascular invasion, and no extra-hepatic metastasis appeared to have longer survival times compared with other cohorts in the present study.

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T Cell–Based Immunotherapy of Metastatic Renal Cell Carcinoma: Modest Success and Future Perspective

Cited by 33 publications

References 99 publications

Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+F4/80+ Cells to Induce Apoptosis of Activated T Cells

Tumor Cell-Released TLR4 Ligands Stimulate Gr-1+CD11b+F4/80+ Cells to Induce Apoptosis of Activated T Cells

T-Cell Receptor Gene–Modified T Cells with Shared Renal Cell Carcinoma Specificity for Adoptive T-Cell Therapy

Efficacy of RetroNectin-activated cytokine-induced killer cell therapy in the treatment of advanced hepatocelluar carcinoma

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