Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015

Pandha, Hardev; Pawelec, Graham

doi:10.1007/s00262-015-1748-7

Cited by 7 publications

(4 citation statements)

References 16 publications

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“…Recently, it has been established that programmed death-1 (PD-1) is a prominent checkpoint receptor that, upon binding its ligands PD-L1 or PD-L2, dampens T effector functions by inhibiting signaling downstream of the T cell receptor [ 4 ]. PD-L2 is predominantly expressed in APCs, whereas PD-L1 is commonly expressed in various cell types, including tumor cells, immune cells, epithelial cells, and endothelial cells [ 1 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

Zheng

Dang

Zha

et al. 2017

BioMed Research International

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Recent studies have indicated that therapeutic antibodies targeting PD-L1 show remarkable efficacy in clinical trials in multiple tumors and that a melanoma cell-intrinsic PD-1: PD-L1 axis promotes tumor growth. However, few studies have shown tumorintrinsic PD-L1 effects in malignant melanoma initiating cells (MMICs). Here, we aim to determine the possible regulatory effects of PD-L1 on MMICs. The ALDEFLUOR kit was used to identify ALDH + MMICs. Flow cytometry was used to examine the expression of PD-L1 on ALDH + MMICs. To determine the role of PD-L1 in MMICs self-renewal, we cultured melanoma cells with anti-PD-L1 and measured tumorsphere formation and apoptosis. In addition, the effects of anti-PD-L1 on tumorigenicity and residual ALDH + MMICs in tumors were evaluated in vivo. We demonstrated that melanoma cell-intrinsic PD-L1 was expressed in ALDH + MMICs. Blocking PD-L1 in melanoma cell lines impaired tumorsphere formation and induced the apoptosis of sphere cells. In addition, blocking PD-L1 inhibited tumor growth in vivo. We observed residual ALDH + MMICs within the tumor. The results showed that blocking PD-L1 also significantly decreased the residual ALDH + MMICs in the tumors. In conclusion, these results suggest a new mechanism underlying melanoma progression and PD-L1-targeted therapy, which is distinct from the immunomodulatory actions of PD-L1.

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Section: Introductionmentioning

confidence: 99%

PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

Zheng

Dang

Zha

et al. 2017

BioMed Research International

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“…Accelerated approval is granted by the FDA for drugs targeting serious or life-threatening diseases where a surrogate marker of efficacy (e.g., progressionfree survival) provides an indication that the drug is "reasonably likely" to benefit patients. Learning how to identify those who will respond and when to offer these products is the next step for applying these novel and potentially lifesaving therapies [38].…”

Section: Resultsmentioning

confidence: 99%

Immuno Oncology: What have the Last 3 Decades Brought?

Baker¹

2015

MOJI

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A little over 30 years ago, the discovery and availability of recombinant growth factors for human lymphocytes, such as IL-2, prompted experimental use of IL-2 to both treat patients directly and for ex vivo expansion of lymphocytes for therapeutic reinfusion. In contrast to the standard practice of immunization, IL-2 therapy represented a pioneering step in developing a course of therapy that involved manipulation of the host immune system. Adoptive immunotherapy produced and still produces some stunning successes but not in all cases and not without the possibility of considerable and severe side effects. The recent approval of Mabs that are checkpoint inhibitors to treat such deadly cancers as melanoma, have opened the door for clinical testing of other Mabs to antigens related to immune surveillance. Adoptive cell immunotherapy has progressed to incorporate elements from adaptive therapy in so far as the cells may be engineered to specifically seek out antigens, as in the CAR-T cell therapy, or may be cultured with markers on specific cancers when appropriately specific antigens are known, such as prostate cancer antigens; MUC1, PAP, PSA, PSMA. Both the development of a range of immunotherapy agents and clinical experience with them continues with the promise to identify how to use this new armory effectively on the war on cancer.

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“…Neoantigens can arise when mutations affect either TCR contact residues or anchor residues in peptide epitopes with affinity for MHC I or II. Even a single amino acid substitution can yield an epitope that is sufficiently different from self to mark tumor cells for T cell mediated destruction [19]. Whole-exome sequencing of NSCLCs treated with pembrolizumab has shown that higher nonsynonymous mutation burdens in tumors were associated with improved objective responses, durable clinical benefit, and improved PFS.…”

Section: Check For Updatesmentioning

confidence: 99%

Improvement in the Selection of Patients for Anti-PD1 Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) Analyzing Tumor Mutational Burden and Retrotransposon Activity as Possible New Biomarker of Effectiveness

Manuel¹

2018

Int J Pathol Clin Res

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Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015

Cited by 7 publications

References 16 publications

PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

PD-L1 Promotes Self-Renewal and Tumorigenicity of Malignant Melanoma Initiating Cells

Immuno Oncology: What have the Last 3 Decades Brought?

Improvement in the Selection of Patients for Anti-PD1 Immunotherapy in Non-Small Cell Lung Cancer (NSCLC) Analyzing Tumor Mutational Burden and Retrotransposon Activity as Possible New Biomarker of Effectiveness

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