A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors.

Infante, Jeffrey R.; Hansen, Aaron Richard; Pishvaian, Michael J.; Chow, Laura Q.; McArthur, Grant A.; Bauer, Todd M.; Liu, Stephen V.; Sandhu, Shahneen; Tsai, Frank; Kim, Jeong; Stefanich, Eric; Li, Chi-Chung; Gilbert, Houston; McCall, Bruce; Anderson, Maria; Huseni, Mahrukh; Rhee, Ina; Siu, Lillian L.; Gordon, Michael

doi:10.1200/jco.2016.34.15_suppl.101

Cited by 65 publications

(44 citation statements)

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“…Because anti-OX40 agonist Ab, already in early phase clinical trials (8), generates strong immune responses (8)(9)(10), the combination of anti-PD-1/PD-L1 Ab and anti-OX40 is an obvious choice for combination immunotherapy. A few clinical trials have already started; others are in the planning stage to test this combination (12,13). However, the immune effect of such a combination and the interaction of the two molecules on the downstream immune outcome remain unclear.…”

Section: Discussionmentioning

confidence: 99%

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Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis

Shrimali

Ahmad

Verma

et al. 2017

Cancer Immunology Research

134

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Combination therapies that depend on checkpoint inhibitor antibodies (Abs) such as for PD-1 or its ligand (PD-L1) together with immune stimulatory agonist Abs like anti-OX40 are being tested in the clinic to achieve improved antitumor effects. Here, we studied the potential therapeutic and immune effects of one such combination: Ab to PD-1 with agonist Ab to OX40/vaccine. We tested the antitumor effects of different treatment sequencing of this combination. We report that simultaneous addition of anti-PD-1 to anti-OX40 negated the antitumor effects of OX40 Ab. Antigen-specific CD8 þ T-cell infiltration into the tumor was diminished, the resultant antitumor response weakened, and survival reduced. Although we observed an increase in IFNgproducing E7-specifc CD8 þ T cells in the spleens of mice treated with the combination of PD-1 blockade with anti-OX40/vaccine, these cells underwent apoptosis both in the periphery and the tumor. These results indicate that anti-PD-1 added at the initiation of therapy exhibits a detrimental effect on the positive outcome of anti-OX40 agonist Ab. These findings have important implications on the design of combination immunotherapy for cancer, demonstrating the need to test treatment combination and sequencing before moving to the clinic.

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Section: Discussionmentioning

confidence: 99%

“…Few clinical trials have started and others are being planned to test this combination. However, response results have not yet been reported (12,13). Further, the potential immune effect of such combination and the interaction of the two molecules on the downstream immune outcome are not fully clear.…”

Section: Introductionmentioning

confidence: 99%

Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis

Shrimali

Ahmad

Verma

et al. 2017

Cancer Immunology Research

134

View full text Add to dashboard Cite

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“…1). Several agonistic biologicals for this stimulatory immune checkpoint have already shown objective responses in phase I clinical trials as mono or combination therapy (Infante et al 2016;El-Khoueiry et al 2017). To complement these therapies, nuclear imaging of the T cell activation marker OX40 might be used to predict OX40 agonist responses or to follow treatment responses that focus on T cell activation.…”

Section: Ox40 Imagingmentioning

confidence: 99%

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Wierstra

Sandker

Aarntzen

et al. 2019

EJNMMI radiopharm. chem.

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Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by noninvasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyteassociated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers.

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“…Other known checkpoint inhibitor receptors, such as Lymphocyte activation gene-3 (LAG3) and T cell immunoglobulin and mucin domain 3(TIM-3), have demonstrated preclinical synergistic activity with anti-PD1 agents and are thus being evaluated in several combination clinical trials [65,66]. Combination with co-stimulatory receptor agonists, such as with OX40 and 4-1BB, have shown preliminary results of tolerability of this approach with toxicities as expected with anti-PD1 monotherapy [67,68]. Such initial demonstration of safety is critical, given known life-threatening complications of systemic inflammatory and immune reaction, as first encountered in the development of an anti-CD28 superagonist antibody TGN1412 [69].…”

Section: Approaches To Augment the Immune Responsementioning

confidence: 99%

Advances in Cancer Immunotherapy in Solid Tumors

Menon

Shin

2016

Cancers

145

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Immunotherapy is heralded as one of the most important advances in oncology. Until recently, only limited immunotherapeutic options were available in selected immunogenic cancers like melanoma and renal cell carcinomas. Nowadays, there is an improved understanding that anti-tumor immunity is controlled by a delicate balance in the tumor microenvironment between immune stimulatory and immune inhibitory pathways. Either by blocking the inhibitory pathways or stimulating the activating pathways that regulate cytotoxic lymphocytes, anti-tumor immunity can be enhanced leading to durable anti-tumor responses. Drugs which block the immune regulatory checkpoints namely the PD-1/PDL1 and CTLA 4 pathway have shown tremendous promise in a wide spectrum of solid and hematological malignancies, significantly improving overall survival in newly diagnosed and heavily pretreated patients alike. Hence there is renewed enthusiasm in the field of immune oncology with current research focused on augmenting responses to checkpoint inhibitors by combination therapy as well as studies looking at other immune modulators and adoptive T cell therapy. In this article, we highlight the key clinical advances and concepts in immunotherapy with particular emphasis on checkpoint inhibition as well as the future direction in this field.

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A phase Ib dose escalation study of the OX40 agonist MOXR0916 and the PD-L1 inhibitor atezolizumab in patients with advanced solid tumors.

Cited by 65 publications

References 0 publications

Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis

Concurrent PD-1 Blockade Negates the Effects of OX40 Agonist Antibody in Combination Immunotherapy through Inducing T-cell Apoptosis

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Advances in Cancer Immunotherapy in Solid Tumors

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