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Update on vaccine development for renal cell cancer.

Chi N, Maranchie JK, Appleman LJ, Storkus WJ - Open Access J Urol (2010)

Bottom Line: Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents.Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival.In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve.

View Article: PubMed Central - PubMed

Affiliation: Department of immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.

ABSTRACT
Renal cell carcinoma (RCC) remains a significant health concern that frequently presents as metastatic disease at the time of initial diagnosis. Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents. Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival. In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve. Based on the integration of increasingly refined immunomonitoring systems in both translational models and clinical trials, allowing for the improved understanding of treatment mechanism(s) of action, further refined (combinational) vaccine protocols are currently being developed and evaluated. This review provides a brief history of RCC vaccine development, discusses the successes and limitations in such approaches, and provides a rationale for developing combinational vaccine approaches that may provide improved clinical benefits to patients with RCC.

No MeSH data available.


Related in: MedlinePlus

Paradigm for effective renal cell carcinoma (RCC) vaccines. Antitumor T cells in patients with RCC are frequently anergic, hyporesponsive, or they may mediate functions that are nonprotective. T effector (Te) and memory (Tm) cells (cumulatively indicated as Te/m) may also be prone to apoptotic death based on conditioning by tumor cells or their elaborated products in vivo. Naive (T0) antitumor T cells may be rendered nonresponsive or exhibit specificities against “subdominant” RCC-associated antigens (RCCAAs) or epitopes that have failed to become activated productively. Furthermore, the vitality and function of antitumor T cells may be inhibited by regulatory T cells and myeloid-derived suppressor cells (MDSCs), particularly in the tumor microenvironment (TME). Effective vaccine formulations would at least partially correct such defects by (re)activating Te/m and promoting their extended survival and delivery into the TME. Importantly, given some plasticity in functional T-cell polarization, effective RCC vaccines may promote a conversion of nontype-1 T-cell responses towards type-1 immunity, which has been commonly associated with improved clinical prognosis. Such vaccine-induced repolarization in T-cell function may foster the breaking of operational tolerance against additional RCCAAs and the cross-priming of a broadly reactive antitumor T-cell repertoire. If sustained (through booster vaccination), this vaccine-initiated T-cell response may extend time to disease recurrence or progression and overall patient survival.
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f1-oaju-2-125: Paradigm for effective renal cell carcinoma (RCC) vaccines. Antitumor T cells in patients with RCC are frequently anergic, hyporesponsive, or they may mediate functions that are nonprotective. T effector (Te) and memory (Tm) cells (cumulatively indicated as Te/m) may also be prone to apoptotic death based on conditioning by tumor cells or their elaborated products in vivo. Naive (T0) antitumor T cells may be rendered nonresponsive or exhibit specificities against “subdominant” RCC-associated antigens (RCCAAs) or epitopes that have failed to become activated productively. Furthermore, the vitality and function of antitumor T cells may be inhibited by regulatory T cells and myeloid-derived suppressor cells (MDSCs), particularly in the tumor microenvironment (TME). Effective vaccine formulations would at least partially correct such defects by (re)activating Te/m and promoting their extended survival and delivery into the TME. Importantly, given some plasticity in functional T-cell polarization, effective RCC vaccines may promote a conversion of nontype-1 T-cell responses towards type-1 immunity, which has been commonly associated with improved clinical prognosis. Such vaccine-induced repolarization in T-cell function may foster the breaking of operational tolerance against additional RCCAAs and the cross-priming of a broadly reactive antitumor T-cell repertoire. If sustained (through booster vaccination), this vaccine-initiated T-cell response may extend time to disease recurrence or progression and overall patient survival.

Mentions: As depicted in Figure 1, therapeutic normalization of type-1, antitumor T-cell-mediated immunity in patients with RCC requires one or more of the following processes to occur: (1) existing tumor antigen-experienced T cells exhibiting anergy or nontype-1 functional polarization need to be reactivated or retrained to become type-1 polarized; (2) the survival and functionality of existing type-1 T cells must be extended; (3) new type-1 effector cells must be “primed” from the naive cohort of T cells (a process that may require the “breaking” of operational tolerance); (4) effective trafficking of renal cell carcinoma – associated antigen (RCCAA)-specific T cells to the tumor microenvironment (TME); and/or (5) blunting of regulatory T cells (Treg) that suppress effector T-cell activation, function, and durability. Each of these immunologic end points may be theoretically achieved via the implementation of tumor-specific vaccines that contain and/or condition antigen-presenting cells (APCs) in situ to assume type-1 function (typically associated with the ability of APCs to differentially secrete interleukin [IL]-12 vs IL-10).23–25 Reports have shown that type-2 “memory” T-cell responses (ie, characterized by strong IL-4 and IL-5 production) may be repolarized toward type-1 immunity in vitro by (re)stimulation with antigenpulsed dendritic cells (DCs) that were preconditioned with proinflammatory cytokines, toll-receptor ligands, and other costimulatory adjuvants.23,26,27 In humans, type-1 effector T cells have exhibited extended survival, function, and conversion into the memory cells when provided signals from CD16+ monocyte-derived DCs.28 Furthermore, type-1 polarized or conditioned DCs appear superior to alternate APC types in their capacity to activate and drive naive T-cell differentiation into type-1 CD4+ and CD8+ T effector cells in vitro and in vivo.23,29,30 Although much of these data have been developed translationally in the context of cell (ie, DC-based) therapeutics, it would also be predicted that cellfree vaccine formulations including the appropriate tumor antigens and conditioning adjuvants would activate APC in situ with similar type-1-polarizing potential.31–33


Update on vaccine development for renal cell cancer.

Chi N, Maranchie JK, Appleman LJ, Storkus WJ - Open Access J Urol (2010)

Paradigm for effective renal cell carcinoma (RCC) vaccines. Antitumor T cells in patients with RCC are frequently anergic, hyporesponsive, or they may mediate functions that are nonprotective. T effector (Te) and memory (Tm) cells (cumulatively indicated as Te/m) may also be prone to apoptotic death based on conditioning by tumor cells or their elaborated products in vivo. Naive (T0) antitumor T cells may be rendered nonresponsive or exhibit specificities against “subdominant” RCC-associated antigens (RCCAAs) or epitopes that have failed to become activated productively. Furthermore, the vitality and function of antitumor T cells may be inhibited by regulatory T cells and myeloid-derived suppressor cells (MDSCs), particularly in the tumor microenvironment (TME). Effective vaccine formulations would at least partially correct such defects by (re)activating Te/m and promoting their extended survival and delivery into the TME. Importantly, given some plasticity in functional T-cell polarization, effective RCC vaccines may promote a conversion of nontype-1 T-cell responses towards type-1 immunity, which has been commonly associated with improved clinical prognosis. Such vaccine-induced repolarization in T-cell function may foster the breaking of operational tolerance against additional RCCAAs and the cross-priming of a broadly reactive antitumor T-cell repertoire. If sustained (through booster vaccination), this vaccine-initiated T-cell response may extend time to disease recurrence or progression and overall patient survival.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3818884&req=5

f1-oaju-2-125: Paradigm for effective renal cell carcinoma (RCC) vaccines. Antitumor T cells in patients with RCC are frequently anergic, hyporesponsive, or they may mediate functions that are nonprotective. T effector (Te) and memory (Tm) cells (cumulatively indicated as Te/m) may also be prone to apoptotic death based on conditioning by tumor cells or their elaborated products in vivo. Naive (T0) antitumor T cells may be rendered nonresponsive or exhibit specificities against “subdominant” RCC-associated antigens (RCCAAs) or epitopes that have failed to become activated productively. Furthermore, the vitality and function of antitumor T cells may be inhibited by regulatory T cells and myeloid-derived suppressor cells (MDSCs), particularly in the tumor microenvironment (TME). Effective vaccine formulations would at least partially correct such defects by (re)activating Te/m and promoting their extended survival and delivery into the TME. Importantly, given some plasticity in functional T-cell polarization, effective RCC vaccines may promote a conversion of nontype-1 T-cell responses towards type-1 immunity, which has been commonly associated with improved clinical prognosis. Such vaccine-induced repolarization in T-cell function may foster the breaking of operational tolerance against additional RCCAAs and the cross-priming of a broadly reactive antitumor T-cell repertoire. If sustained (through booster vaccination), this vaccine-initiated T-cell response may extend time to disease recurrence or progression and overall patient survival.
Mentions: As depicted in Figure 1, therapeutic normalization of type-1, antitumor T-cell-mediated immunity in patients with RCC requires one or more of the following processes to occur: (1) existing tumor antigen-experienced T cells exhibiting anergy or nontype-1 functional polarization need to be reactivated or retrained to become type-1 polarized; (2) the survival and functionality of existing type-1 T cells must be extended; (3) new type-1 effector cells must be “primed” from the naive cohort of T cells (a process that may require the “breaking” of operational tolerance); (4) effective trafficking of renal cell carcinoma – associated antigen (RCCAA)-specific T cells to the tumor microenvironment (TME); and/or (5) blunting of regulatory T cells (Treg) that suppress effector T-cell activation, function, and durability. Each of these immunologic end points may be theoretically achieved via the implementation of tumor-specific vaccines that contain and/or condition antigen-presenting cells (APCs) in situ to assume type-1 function (typically associated with the ability of APCs to differentially secrete interleukin [IL]-12 vs IL-10).23–25 Reports have shown that type-2 “memory” T-cell responses (ie, characterized by strong IL-4 and IL-5 production) may be repolarized toward type-1 immunity in vitro by (re)stimulation with antigenpulsed dendritic cells (DCs) that were preconditioned with proinflammatory cytokines, toll-receptor ligands, and other costimulatory adjuvants.23,26,27 In humans, type-1 effector T cells have exhibited extended survival, function, and conversion into the memory cells when provided signals from CD16+ monocyte-derived DCs.28 Furthermore, type-1 polarized or conditioned DCs appear superior to alternate APC types in their capacity to activate and drive naive T-cell differentiation into type-1 CD4+ and CD8+ T effector cells in vitro and in vivo.23,29,30 Although much of these data have been developed translationally in the context of cell (ie, DC-based) therapeutics, it would also be predicted that cellfree vaccine formulations including the appropriate tumor antigens and conditioning adjuvants would activate APC in situ with similar type-1-polarizing potential.31–33

Bottom Line: Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents.Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival.In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve.

View Article: PubMed Central - PubMed

Affiliation: Department of immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States.

ABSTRACT
Renal cell carcinoma (RCC) remains a significant health concern that frequently presents as metastatic disease at the time of initial diagnosis. Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents. Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival. In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve. Based on the integration of increasingly refined immunomonitoring systems in both translational models and clinical trials, allowing for the improved understanding of treatment mechanism(s) of action, further refined (combinational) vaccine protocols are currently being developed and evaluated. This review provides a brief history of RCC vaccine development, discusses the successes and limitations in such approaches, and provides a rationale for developing combinational vaccine approaches that may provide improved clinical benefits to patients with RCC.

No MeSH data available.


Related in: MedlinePlus