Combination strategies to maximize the benefits of cancer immunotherapy

Zhu, Shaoming; Zhang, Tian; Li, Zheng; Liu, Hongtao; Song, Wenru; Liu, Delong; Li, Zihai; Pan, Chong‐Xian

doi:10.1186/s13045-021-01164-5

Cited by 313 publications

(235 citation statements)

References 313 publications

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“…Therefore, it may be difficult to achieve promising results by simply blocking PD-1/PD-L1 signaling alone. Combination of PD-1/PD-L1 inhibitor with other ICIs has been suggested [ 76 , 164 – 167 ]. Other immune checkpoints (Fig.…”

Section: Future Perspectivesmentioning

confidence: 99%

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Yang

Zhang

et al. 2022

Exp Hematol Oncol

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Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), and approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic hematopoietic clones and poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver of MDS and AML, causing high rate of intramedullary apoptosis in lower-risk MDS to immunosuppression in higher-risk MDS and AML. Immune checkpoint molecules, including programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), play important roles in oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have been examined in MDS and AML. Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, and treatment of patients all have been involved in dysregulating PD-1/PD-L1 signaling in these two diseases. Furthermore, with the PD-1/PD-L1 pathway activated in immune microenvironment, the milieu of BM shift to immunosuppressive, contributing to a clonal evolution of blasts. Nevertheless, numerous preclinical studies have suggested a potential response of patients to PD-1/PD-L1 blocker. Current clinical trials employing these drugs in MDS and AML have reported mixed clinical responses. In this paper, we focus on the recent preclinical advances of the PD-1/PD-L1 signaling in MDS and AML, and available and ongoing outcomes of PD-1/PD-L1 inhibitor in patients. We also discuss the novel PD-1/PD-L1 blocker-based immunotherapeutic strategies and challenges, including identifying reliable biomarkers, determining settings, and exploring optimal combination therapies.

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Section: Future Perspectivesmentioning

confidence: 99%

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Yang

Zhang

et al. 2022

Exp Hematol Oncol

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“…However, not all patients respond to ICIs and the overall response rate (ORR) varies by tumor type and agent [ 3 ], ranging from 10.9% for single-agent ipilimumab in previous treated melanoma [ 4 ] to 69% for pembrolizumab in relapsed/refractory classic Hodgkin’s lymphoma [ 5 ], with a subset of patients developing resistance over time [ 1 ]. To increase response and combat resistance, combinations of ICIs with each other or with treatments such as chemotherapy, radiation, and targeted therapy are increasingly being used which increases the complexity of toxicity [ 6 ]. The use of ICIs is rapidly expanding.…”

Section: Introductionmentioning

confidence: 99%

Immune Checkpoint Inhibitors—Associated Cardiotoxicity

Bhatti

Ying

2022

Cancers

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Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49–2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01–1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85–4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies.

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“…DC/PD-1 immunotherapy combinations are currently under preclinical and clinical investigation in recurrent advanced brain tumors, advanced and relapsed NSCLC, MM and advanced renal cell carcinoma [ 151 ]. Additionally, various other combination therapies that exploit alternative immune targets and other therapeutic modalities have been explored for cancer treatment [ 152 – 154 ], especially with the development of a new generation of immune checkpoint inhibitors and other inhibitory targets [ 155 – 161 ]. The combination of a DC/AML cell fusion vaccine and checkpoint blocking therapy provides unique synergy to induce durable activation of leukemia specific immunity, protect against lethal tumor challenges, and selectively amplify tumor-reactive clones [ 162 ].…”

Section: Enhancing DC Vaccine Efficacy Via Coadministration With Chemotherapy and Checkpoint Inhibitorsmentioning

confidence: 99%

Research progress on dendritic cell vaccines in cancer immunotherapy

Sun

Cao

et al. 2022

Exp Hematol Oncol

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Dendritic cell (DC) vaccines induce specific immune responses that can selectively eliminate target cells. In recent years, many studies have been conducted to explore DC vaccination in the treatment of hematological malignancies, including acute myeloid leukemia and myelodysplastic syndromes, as well as other nonleukemia malignancies. There are at least two different strategies that use DCs to promote antitumor immunity: in situ vaccination and canonical vaccination. Monocyte-derived DCs (mo-DCs) and leukemia-derived DCs (DCleu) are the main types of DCs used in vaccines for AML and MDS thus far. Different cancer-related molecules such as peptides, recombinant proteins, apoptotic leukemic cells, whole tumor cells or lysates and DCs/DCleu containing a vaster antigenic repertoire with RNA electroporation, have been used as antigen sources to load DCs. To enhance DC vaccine efficacy, new strategies, such as combination with conventional chemotherapy, monospecific/bispecific antibodies and immune checkpoint-targeting therapies, have been explored. After a decade of trials and tribulations, much progress has been made and much promise has emerged in the field. In this review we summarize the recent advances in DC vaccine immunotherapy for AML/MDS as well as other nonleukemia malignancies.

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Combination strategies to maximize the benefits of cancer immunotherapy

Cited by 313 publications

References 313 publications

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Immune Checkpoint Inhibitors—Associated Cardiotoxicity

Research progress on dendritic cell vaccines in cancer immunotherapy

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