Targeting the programmed cell death-1 pathway in breast and ovarian cancer

Emens, Leisha A.; Kok, Marleen; Ojalvo, Laureen S.

doi:10.1097/gco.0000000000000257

Cited by 52 publications

(47 citation statements)

References 29 publications

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“…Expression of PD-L1 on breast tumors cells as well as on associated stromal cells has also been extensively studied by analyzing pathological specimens (2). This is important because the binding of PD-L1 to PD-1 on the surface of infiltrating T cells can lead to T cell inactivation or exhaustion.…”

Section: Pd-1/pd-l1 In Human Breast Cancermentioning

confidence: 99%

Immunotherapy for Breast Cancer: What Are We Missing?

Vonderheide

Domchek

Clark

2017

Clinical Cancer Research

177

146

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The recent demonstration of modest single-agent activity of programmed death-ligand 1 (PD-L1) and programmed death receptor-1 (PD-1) antibodies in patients with breast cancer has generated hope that breast cancer can be made amenable to immunotherapy. Depending on the subtype of breast cancer, it is now clear in both primary and metastatic disease that the extent of tumor-infiltrating T cells is not only prognostic for survival but predictive of response to non-immune, standard therapies. Despite these findings, immune cytolytic activity in spontaneous breast tumors, the burden of nonsynonymous tumor mutations, and the predicted load of neo-epitopes – factors linked to response to checkpoint blockade in other malignancies – are all relatively modest in breast cancer, compared to melanoma or lung cancer. Thus, in breast cancer, combinations of immune agents with non-redundant mechanisms of action are the high-priority strategies. For most breast cancers that exhibit relatively modest T cell infiltration, major challenges include immune suppression in the tumor microenvironment as well as failed or suboptimal T cell priming. Agents that trigger de novo T cell responses may be critical for successful development of cancer immunotherapy and immune prevention in breast cancer. Success may also require reaching beyond nonsynonymous mutations as the T cell epitopes to target, especially as numerous unmutated proteins were validated as breast cancer associated antigens in the pre-checkpoint era. A deeper understanding of the immunobiology of breast cancer will be critical for immunotherapy to become broadly relevant in this disease.

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Section: Pd-1/pd-l1 In Human Breast Cancermentioning

confidence: 99%

Immunotherapy for Breast Cancer: What Are We Missing?

Vonderheide

Domchek

Clark

2017

Clinical Cancer Research

177

146

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“…Adding to this interest, tumor-infiltrating lymphocytes (TIL) have been shown to associate with good clinical outcome (21) and response to therapy (22). PD-1 expression on TIL and PD-L1 expression on breast cancer tumors is associated with worse prognosis (23,24) and preliminary results of clinical trials with PD-1 blockade have produced objective responses in specific subsets of patients (25). However, overall responses have been modest (5–19%), leaving a majority of patients refractory to monotherapy.…”

Section: Introductionmentioning

confidence: 99%

Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Messenheimer

Jensen

Afentoulis

et al. 2017

Clinical Cancer Research

272

183

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Purpose Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to impact patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T cell costimulatory receptors such as OX40 remains a critical question. Experimental Design We utilized an anti-PD-1 refractory, orthotopically-transplanted MMTV-PyMT mammary cancer model to investigate the anti-tumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. Since PD-1 naturally aids in immune contraction after T cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1. Results The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type 1 and type 2 serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4+ T cell proliferation at day 13, but at day 19 both CD4+ and CD8+ T cell proliferation was significantly reduced compared to untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors sequential combination was dependent on both CD4+ and CD8+ T cells and completely regressed tumors in ~30% of treated animals. Conclusions These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials.

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“…Very limited data are currently available about the activity of immune checkpoint inhibitors in gynecological cancers; however, immune checkpoint inhibitors, and especially anti-PD-1 and anti-PD-L1 mAbs, could represent a novel pharmacological tool for the management of gynecological malignancies, although is yet to be defined which patients could draw a greater clinical benefit from these agents and when immunecheckpointinhibitors should be incorporated into the therapeutic strategy (37,108,109). Moreover, reliable biomarkers predictive of response have not been identified yet.…”

Section: Resultsmentioning

confidence: 99%

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

2017

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Targeting the programmed cell death-1 pathway in breast and ovarian cancer

Cited by 52 publications

References 29 publications

Immunotherapy for Breast Cancer: What Are We Missing?

Immunotherapy for Breast Cancer: What Are We Missing?

Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

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