PD-1/PD-L1 inhibitors in multiple myeloma: The present and the future

Jelı́nek, Tomáš

doi:10.1080/2162402x.2016.1254856

Cited by 39 publications

(38 citation statements)

References 53 publications

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“…Anti‐PD‐1 mAbs are represented mainly by nivolumab (OPDIVO, MDX1106, BMS‐936558; Bristol‐Myers Squibb, New York City, NY, USA) – a fully human IgG4 mAb; pembrolizumab (KEYTRUDA, MK‐3475; Merck, Kenilworth, NJ, USA) – a highly selective humanized IgG4 mAb and pidilizumab (MDV9300, CT‐011; Medivation/Pfizer, New York City, NY, USA) – an IgG1 mAb. Within the anti‐PD‐L1 mAbs, the most promising are durvalumab (Celgene, Summit, NJ, USA) and atezolizumab (Roche, Basel, Switzerland), which have just entered the early phases of clinical testing …”

Section: Introductionmentioning

confidence: 99%

PD‐1/PD‐L1 inhibitors in haematological malignancies: update 2017

et al. 2017

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The introduction of PD-1/PD-L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice-changing activity in various types of solid tumours. Among haematological malignancies, PD-1/PD-L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over-expression of PD-1 ligands (PD-L1, PD-L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication. Although the results in other lymphoid malignancies have not been so striking, blockade of the PD-1/PD-L1 axis has led to meaningful responses in other lymphoma types such as diffuse large B-cell lymphoma, follicular lymphoma or several T-cell lymphomas. Monotherapy with PD-1/PD-L1 inhibitors in chronic lymphocytic leukaemia and multiple myeloma has been unsatisfactory, suggesting that a combinational approach with other synergistic drugs is needed. In the case of multiple myeloma, immunomodulatory agents together with corticosteroids represent the most promising combinations. Among myeloid malignancies, the anti-PD-1 monoclonal antibodies are examined dominantly in acute myeloid leukaemia and myelodysplastic syndromes in combination with potentially synergistic hypomethylating drugs such as 5-azacitidine, resulting in promising outcomes that warrant further investigation. We have described all available clinical results of PD-1/PD-L1 inhibitors in haematological malignancies and discussed related toxicities, as well as highlighted crucial preclinical studies in this review.

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Section: Introductionmentioning

confidence: 99%

PD‐1/PD‐L1 inhibitors in haematological malignancies: update 2017

et al. 2017

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“…Several studies have shown that PD-L1 is expressed on plasma cells but also on DC in the bone marrow, with a various intensity of PDL-1 expression among patients. [13][14][15][16]21 Furthermore, PD-L1-expressing pDC are increased and localized with PD-L1-positive MM cells in bone marrow. 19 Importantly, PD-L1 expression correlates with progression of disease, with the highest levels of expression in relapsed or relapsed/refractory MM.…”

Section: Discussionmentioning

confidence: 98%

“…Recently, Chen et al demonstrated that CD38 upregulation in tumors induces resistance to PD‐1/PD‐L1 blocking antibodies and coinhibition of CD38 and PD‐L1 improves antitumor immune response. Several studies have shown that PD‐L1 is expressed on plasma cells but also on DC in the bone marrow, with a various intensity of PDL‐1 expression among patients . Furthermore, PD‐L1‐expressing pDC are increased and localized with PD‐L1‐positive MM cells in bone marrow .…”

Section: Discussionmentioning

confidence: 99%

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

et al. 2020

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Background Daratumumab (Dara), an anti‐CD38 monoclonal antibody, has an immunologic mechanism of action through targeting of CD38 expressing immune cells in patients with multiple myeloma (MM). Furthermore, it was recently shown that CD38 upregulation in tumors, is a major mechanism of acquired resistance to antiprogrammed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1). Therefore, we decided to evaluate the immunomodulatory effects of CD38 blockade by Dara on the PD‐L1 expressing immune cells. Methods We analyzed CD38 and PD‐L1 expression on immune cells at different time points in 18 newly diagnosed MM receiving bortezomib, lenalidomide and dexamethasone, with or without Dara. Results We first confirmed that CD38 is widely expressed on immune cells, with the strongest expression on plasmacytoid dendritic cells (pDC). Furthermore, Dara induces a strong depletion of pDC in addition to the well‐known rapid depletion of natural killer cells. Finally, we found that PD‐L1 expression on antigen‐presenting cells (APC) increases with MM treatment in patients that did not received Dara, while addition of Dara prevents this increase. Conclusion Overall, our results suggest new mechanisms of action of Dara through depletion of pDC and prevention of PD‐L1 upregulation expression on APC. Our finding provides new evidences for development of therapeutic strategies targeting both CD38 and PD‐L1/PD‐1 pathway in patients with MM.

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“…183,185-187 In several instances, vaccination is further combined with standard treatment regimens including conventional chemotherapy, 117,188-191 radiation therapy, 52,192-195 and targeted anticancer agents, 196-199 or with various immunotherapeutic interventions. 200-205 The latter include (1) immune checkpoint blockers such as the anti-PD-1 mAbs pembrolizumab and nivolumab, 206-208 the anti-PD-L1 mAbs durvalumab and atezolizumab, 209-211 and the anti-CTLA4 mAb ipilimumab; 137,186,212-215 (2) immunostimulatory antibodies such as utomilumab, which stimulates TNF receptor superfamily member 9 (TNFRSF9; best known as 4-1BB or CD137) signaling, 28,216-218 or the CD27 agonist varlilumab; 28,216,219,220 and immunomodulatory agents such as lenalidomide. 221-224 In line with preclinical and clinical data demonstrating that multi-epitope vaccines are generally more powerful than their single-epitope counterparts, 117,225 the most common vaccination strategy employed by these studies consists in targeting simultaneously multiple TAAs (20 studies).…”

Section: Ongoing Clinical Trialsmentioning

confidence: 99%

Trial watch: Peptide-based vaccines in anticancer therapy

et al. 2018

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Peptide-based anticancer vaccination aims at stimulating an immune response against one or multiple tumor-associated antigens (TAAs) following immunization with purified, recombinant or synthetically engineered epitopes. Despite high expectations, the peptide-based vaccines that have been explored in the clinic so far had limited therapeutic activity, largely due to cancer cell-intrinsic alterations that minimize antigenicity and/or changes in the tumor microenvironment that foster immunosuppression. Several strategies have been developed to overcome such limitations, including the use of immunostimulatory adjuvants, the co-treatment with cytotoxic anticancer therapies that enable the coordinated release of damage-associated molecular patterns, and the concomitant blockade of immune checkpoints. Personalized peptide-based vaccines are also being explored for therapeutic activity in the clinic. Here, we review recent preclinical and clinical progress in the use of peptide-based vaccines as anticancer therapeutics.Abbreviations: CMP: carbohydrate-mimetic peptide; CMV: cytomegalovirus; DC: dendritic cell; FDA: Food and Drug Administration; HPV: human papillomavirus; MDS: myelodysplastic syndrome; MHP: melanoma helper vaccine; NSCLC: non-small cell lung carcinoma; ODD: orphan drug designation; PPV: personalized peptide vaccination; SLP: synthetic long peptide; TAA: tumor-associated antigen; TNA: tumor neoantigen

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PD-1/PD-L1 inhibitors in multiple myeloma: The present and the future

Cited by 39 publications

References 53 publications

PD‐1/PD‐L1 inhibitors in haematological malignancies: update 2017

PD‐1/PD‐L1 inhibitors in haematological malignancies: update 2017

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

Trial watch: Peptide-based vaccines in anticancer therapy

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