The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with ...poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment.
Chimeric antigen receptor (CAR) T cell therapies have demonstrated remarkable efficacy for the treatment of hematological malignancies. However, in patients with solid tumors, objective responses to ...CAR-T cell therapy remain sporadic and transient. A major obstacle for CAR-T cells is the intrinsic ability of tumors to evade immune responses. Advanced solid tumors are largely composed of desmoplastic stroma and immunosuppressive modulators, and characterized by aberrant cell proliferation and vascularization, resulting in hypoxia and altered nutrient availability. To mount a curative response after infusion, CAR-T cells must infiltrate the tumor, recognize their cognate antigen and perform their effector function in this hostile tumor microenvironment, to then differentiate and persist as memory T cells that confer long-term protection. Fortunately, recent advances in synthetic biology provide a wide set of tools to genetically modify CAR-T cells to overcome some of these obstacles. In this review, we provide a comprehensive overview of the key tumor intrinsic mechanisms that prevent an effective CAR-T cell antitumor response and we discuss the most promising strategies to prevent tumor escape to CAR-T cell therapy.
Single-agent PD-1 blockade exhibits limited efficacy in epithelial ovarian cancer (EOC). We evaluated ipilimumab plus nivolumab compared with nivolumab alone in women with persistent or recurrent ...EOC.
Eligibility criteria included measurable disease, 1-3 prior regimens, and platinum-free interval (PFI) < 12 months. Participants were randomly allocated to intravenous nivolumab (every 2 weeks) or induction with nivolumab plus ipilimumab for 4 doses (every 3 weeks), followed by every-2-week maintenance nivolumab for a maximum of 42 doses. The primary null hypothesis was equal probability of objective response within 6 months of random allocation in each arm.
One hundred patients were allocated to receive either nivolumab (n = 49), or nivolumab plus ipilimumab (n = 51), with PFI of < 6 months in 62%. Six (12.2%) responses occurred within 6 months in the nivolumab group and 16 (31.4%) in the nivolumab plus ipilimumab group (odds ratio, 3.28; 85% CI, 1.54 to infinity;
= .034). The median progression-free survival (PFS) was 2 and 3.9 months in the nivolumab and nivolumab plus ipilimumab groups, respectively, with a PFI-stratified hazard ratio of 0.53 (95% CI, 0.34 to 0.82); the respective hazard ratio for death was 0.79 (95% CI, 0.44 to 1.42). Grade ≥ 3 related adverse events occurred in 33% of patients in the nivolumab group and 49% in the combination group, with no treatment-related deaths. PD-L1 expression was not significantly associated with response in either treatment group.
Compared with nivolumab alone, the combination of nivolumab and ipilimumab in EOC resulted in superior response rate and longer, albeit limited, PFS, with toxicity of the combination regimen comparable to prior reports. Additional combination studies to enhance durability of the dual regimen are warranted.
T cells expressing a chimeric antigen receptor (CAR) can produce dramatic results in lymphocytic leukemia patients; however, therapeutic strategies for myeloid leukemia remain limited. Folate ...receptor β (FRβ) is a myeloid-lineage antigen expressed on 70% of acute myeloid leukemia (AML) patient samples. Here, we describe the development and evaluation of the first CARs specific for human FRβ (m909) in vitro and in vivo. m909 CAR T cells exhibited selective activation and lytic function against engineered C30-FRβ as well as endogenous FRβ+ AML cell lines in vitro. In mouse models of human AML, m909 CAR T cells mediated the regression of engrafted FRβ+ THP1 AML in vivo. In addition, we demonstrated that treatment of AML with all-trans retinoic acid (ATRA) enhanced FRβ expression, resulting in improved immune recognition by m909 CAR T cells. Because many cell surface markers are shared between AML blasts and healthy hematopoietic stem and progenitor cells (HSCs), we evaluated FRβ expression and recognition of HSCs by CAR T cells. m909 CAR T cells were not toxic against healthy human CD34+ HSCs in vitro. Our results indicate that FRβ is a promising target for CAR T-cell therapy of AML, which may be augmented by combination with ATRA.
•Human FRβ-specific CAR T cells target AML in vitro and in vivo without toxicity against healthy bone marrow HSCs.•Combination with ATRA-mediated receptor upregulation may augment FRβ-directed CAR therapy of AML.
Adoptive immunotherapy for cancer: building on success Gattinoni, Luca; Restifo, Nicholas P; Powell, Daniel J ...
Nature Reviews: Immunology,
200605, 2006-May, 2006-05-01, 20060501, Letnik:
6, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Adoptive cell transfer after host preconditioning by lymphodepletion represents an important advance in cancer immunotherapy. Here, we describe how a lymphopaenic environment enables tumour-reactive ...T cells to destroy large burdens of metastatic tumour and how the state of differentiation of the adoptively transferred T cells can affect the outcome of treatment. We also discuss how the translation of these new findings might further improve the efficacy of adoptive cell transfer through the use of vaccines, haematopoietic-stem-cell transplantation, modified preconditioning regimens, and alternative methods for the generation and selection of the T cells to be transferred.
The immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of ...the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ
TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8
T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ
TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.
We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell ...infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.
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•CD8+ T cell infiltration in tumors is associated with CCL5 and CXCL9 coexpression•CCL5 is expressed in tumor cells and CXCL9 is induced in APCs in response to IFN-γ•CCL5hiCXCL9hi tumors are immunoreactive and respond to checkpoint blockade•Cancer cells negatively regulate CCL5 expression by epigenetic silencing mechanisms
Dangaj et al. show that tumor cell-expressed CCL5 and macrophage- and DC-expressed CXCL9 are important for the infiltration of T cells into tumors, a process that also requires recognition of tumor antigens by T cells. CCL5 is often epigenetically silenced in tumor cells but can be reactivated by Decitabine.
The detection of tumor‐specific T cells in solid tumors is integral to interrogate endogenous antitumor responses and to advance downstream therapeutic applications. Multiple biomarkers are reported ...to identify endogenous tumor‐specific tumor‐infiltrating lymphocytes (TILs), namely CD137, PD‐1, CD103, and CD39; however, a direct comparison of these molecules has yet to be performed. We evaluated these biomarkers in primary human ovarian tumor samples using single‐cell mass cytometry to compare their relative phenotypic profiles, and examined their response to autologous tumor cells ex vivo. PD‐1+, CD103+, and CD39+ TILs all contain a CD137+ cell subset, while CD137+ TILs highly co‐express the aforementioned markers. CD137+ TILs exhibit the highest expression of cytotoxic effector molecules compared to PD‐1+, CD103+, or CD39+ TILs. Removal of CD137+ cells from PD‐1+, CD103+, or CD39+ TILs diminish their IFN‐γ secretion in response to autologous tumor cell stimulation, while CD137+ TILs maintain high HLA‐dependent IFN‐γ secretion. CD137+ TILs exhibited an exhausted phenotype but with CD28 co‐expression, suggesting possible receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD‐1+, CD103+, and CD39+ TILs are mainly derived from a subset of CD137‐expressing TILs, implicating CD137 as a more selective biomarker for naturally occurring tumor‐specific TILs.
High dimensional immunophenotyping and autologous tumor stimulation of human tumor‐infiltrating lymphocytes (TILs) demonstrate that the tumor‐specificity of PD‐1+, CD103+, and CD39+ TIL subsets are mainly derived from TILs expressing CD137. These results indicate that CD137 is a more selective biomarker for naturally‐occurring, tumor‐specific TILs in solid human tumors.
Immunotherapy for ovarian cancer: what's next? Kandalaft, Lana E; Powell, Jr, Daniel J; Singh, Nathan ...
Journal of clinical oncology,
03/2011, Letnik:
29, Številka:
7
Journal Article
Recenzirano
Odprti dostop
In the past decade, we have witnessed important gains in the treatment of ovarian cancer; however, additional advances are required to reduce mortality. With compelling evidence that ovarian cancers ...are immunogenic tumors, immunotherapy should be further pursued and optimized. The dramatic advances in laboratory and clinical procedures in cellular immunotherapy, along with the development of powerful immunomodulatory antibodies, create new opportunities in ovarian cancer therapeutics. Herein, we review current progress and future prospects in vaccine and adoptive T-cell therapy development as well as immunomodulatory therapy tools available for immediate clinical testing.
Although ovarian cancer patients typically respond to standard of care therapies, including chemotherapy and DNA repair inhibitors, the majority of tumors recur highlighting the need for alternative ...therapies. Ovarian cancer is an immunogenic cancer in which the accumulation of tumor infiltrating lymphocytes (TILs), particularly T cells, is associated with better patient outcome. Thus, harnessing the immune system through passive administration of T cells, a process called adoptive cell therapy (ACT), is a promising therapeutic option for the treatment of ovarian cancer. There are multiple routes by which tumor-specific T cell products can be generated. Dendritic cell cancer vaccines can be administered to the patients to induce or bolster T cell responses against tumor antigens or be utilized ex vivo to prime T cells against tumor antigens; these T cells can then be prepared for infusion. ACT protocols can also utilize naturally-occurring tumor-reactive T cells isolated from a patient tumor, known as TILs, as these cells often are heterogeneous in composition and antigen specificity with patient-specific cancer recognition. Alternatively, T cells may be sourced from the peripheral blood, including those that are genetically modified to express a tumor antigen-specific T cell receptor (TCR) or chimeric antigen receptor (CAR) to redirect their specificity and promote their activity against tumor cells expressing the target tumor antigen. Here, we review current ACT strategies for ovarian cancer and provide insights into advancing ACT therapy strategies for the treatment of ovarian cancer.
•Ovarian cancer is immunogenic and tumor infiltrating lymphocytes (TILs) are a prognostic biomarker for patient outcomes.•Adoptive cell therapies (ACTs) are promising therapeutic approaches for ovarian cancer.•Optimization of ACT strategies in ovarian cancer is needed for increased clinical efficacy and safety.
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