Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment

Gajewski, Thomas F.; Woo, Seng-Ryong; Zha, Yuanyuan; Spaapen, Robbert M.; Zheng, Yan; Corrales, Leticia; Spranger, Stefani

doi:10.1016/j.coi.2013.02.009

Cited by 372 publications

(310 citation statements)

References 93 publications

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“…4B). Infiltration of CD8 T cells is relevant because previous immunotherapies such as tumor antigen-specific vaccines may have failed due to poor trafficking of these cells into the tumor (11). NK cell responses are also mobilized by NKTR-214 treatment; both innate and adaptive immune responses appear to play a role in antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

“…4A). Overcoming immune tolerance in the tumor microenvironment may require tipping the balance in favor of CD8 T over Tregs in the tumor (10)(11)(12)(13). Furthermore, CD8 T cells are extensively interspersed with tumor cells (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…IL2 also binds to its heterotrimeric receptor IL2Rabg with greater affinity, which expands immunosuppressive CD4 þ CD25 þ regulatory T cells (Tregs) expressing high constitutive levels of IL2Ra. Expansion of Tregs represents an undesirable effect of IL2 for cancer immunotherapy (7)(8)(9)(10)(11)(12)(13). We hypothesized IL2 conjugation with polyethylene glycol (PEG) could be used to mask the region of IL2 that interacts with the IL2Ra subunit responsible for activating immunosuppressive Tregs, biasing activity towards tumor killing CD8 þ T cells.…”

Section: Introductionmentioning

confidence: 99%

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NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

Charych

Hoch

Langowski

et al. 2016

Clinical Cancer Research

343

298

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Purpose: Aldesleukin, recombinant human IL2, is an effective immunotherapy for metastatic melanoma and renal cancer, with durable responses in approximately 10% of patients; however, severe side effects limit maximal dosing and thus the number of patients able to receive treatment and potential cure. NKTR-214 is a prodrug of conjugated IL2, retaining the same amino acid sequence as aldesleukin. The IL2 core is conjugated to 6 releasable polyethylene glycol (PEG) chains. In vivo, the PEG chains slowly release to generate active IL2 conjugates.Experimental Design: We evaluated the bioactivity and receptor binding of NKTR-214 and its active IL2 conjugates in vitro; the tumor immunology, tumor pharmacokinetics, and efficacy of NKTR-214 as a single agent and in combination with anti-CTLA-4 antibody in murine tumor models. Tolerability was evaluated in non-human primates.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

Charych

Hoch

Langowski

et al. 2016

Clinical Cancer Research

343

298

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“…Even when antitumor T cells are generated, trafficking to the tumor site may be limited. 1 This can be improved by using appropriate vaccine administration routes, allowing targeting of relevant tumor sites through specific mucosal homing or cancer site retention programs. [2][3][4][5] An alternative approach, irrespective of the immunization route, is to enhance T-cell attraction to the tumor site through the local application of selected chemokines 6 or Toll-like receptor (TLR) agonists that are able to modify the expression of selectins, integrins, chemokines, and chemokine receptors.…”

Section: Introductionmentioning

confidence: 99%

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

et al. 2015

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The efficacy of antitumoral responses can be increased using combinatorial vaccine strategies. We recently showed that vaccination could be optimized by local administration of diverse molecular or bacterial agents to target and augment antitumoral CD8 T cells in the genital mucosa (GM) and increase regression of cervical cancer in an animal model. Non muscle-invasive bladder cancer is another disease that is easily amenable to local therapies. In contrast to data obtained in the GM, in this study we show that intravesical (IVES) instillation of synthetic toll-like receptor (TLR) agonists only modestly induced recruitment of CD8 T cells to the bladder. However, IVES administration of Ty21a, a live bacterial vaccine against typhoid fever, was much more effective and increased the number of total and vaccinespecific CD8 T cells in the bladder approximately 10 fold. Comparison of chemokines induced in the bladder by either CpG (a TLR-9 agonist) or Ty21a highlighted the preferential increase in complement component 5a, CXCL5, CXCL2, CCL8, and CCL5 by Ty21a, suggesting their involvement in the attraction of T cells to the bladder. IVES treatment with Ty21a after vaccination also significantly increased tumor regression compared to vaccination alone, resulting in 90% survival in an orthotopic murine model of bladder cancer expressing a prototype tumor antigen. Our data demonstrate that combining vaccination with local immunostimulation may be an effective treatment strategy for different types of cancer and also highlight the great potential of the Ty21a vaccine, which is routinely used worldwide, in such combinatorial therapies.

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“…Mechanistic experiments revealed that endogenous IFN-b is produced by CD11c + dendritic cells (DCs) in response to tumor presence, which in turn acts on the CD8a + DC lineage to promote crosspriming of tumor Ag-specific CD8 + T cells in vivo (5). This type I IFN-dependent innate tumor recognition pathway appears crucial for directing the initial adaptive immune response against several murine tumors but is not always sufficient to enable tumor regression, largely because of the upregulation of immune inhibitory mechanisms that also come into play (6)(7)(8). As one strategy to boost this type I IFN production in the tumor microenvironment, we generated conjugates of IFN-b coupled to tumor-targeting mAbs.…”

mentioning

confidence: 99%

Therapeutic Activity of High-Dose Intratumoral IFN-β Requires Direct Effect on the Tumor Vasculature

Spaapen

Leung

Fuertes

et al. 2014

The Journal of Immunology

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Endogenous type I IFN production after innate immune recognition of tumor cells is critical for generating natural adaptive immune responses against tumors in vivo. We recently have reported that targeting low doses of IFN-β to the tumor microenvironment using tumor-specific mAbs can facilitate antitumor immunity, which could be augmented further with PD-L1/PD-1 blockade. However, sustained high doses of type I IFNs in the tumor microenvironment, which are potently therapeutic alone, may function through distinct mechanisms. In the current report, we demonstrate that high-dose intratumoral type I IFNs indeed exerted a profound therapeutic effect in the murine B16 model, which unexpectedly did not increase T cell responses. Moreover, bone marrow chimeras revealed a role for type I IFN signaling on nonhematopoietic cells, and most of the therapeutic effect was retained in mice deficient in T, B, and NK cells. Rather, the tumor vasculature was ablated with high-dose intratumoral IFN-β, and conditional deletion of IFN-α/βR in Tie2-positive vascular endothelial cells eliminated most of the antitumor activity. Therefore, the major component of the antitumor activity of sustained high doses of type I IFNs occurs through a direct antiangiogenic effect. Our data help resolve conditions under which distinct antitumor mechanisms of type I IFNs are operational in vivo.

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Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment

Cited by 372 publications

References 93 publications

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

NKTR-214, an Engineered Cytokine with Biased IL2 Receptor Binding, Increased Tumor Exposure, and Marked Efficacy in Mouse Tumor Models

LocalSalmonellaimmunostimulation recruits vaccine-specific CD8 T cells and increases regression of bladder tumor

Therapeutic Activity of High-Dose Intratumoral IFN-β Requires Direct Effect on the Tumor Vasculature

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