China
Africa
Explore chapters and articles related to this topic
Drug Delivery
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Gudrun Fleischhack, Martin Garnett, Kévin Beccaria
Immunotherapy is a young and exciting field of cancer treatment with the potential to change the standard-of-care therapy across multiple cancers, including CNS tumors. Different immunotherapeutic strategies are followed as single or combined approaches, especially in order to overcome the worst prognosis of high-grade gliomas in adults and children, but are also pursued in other highly malignant CNS tumors: (1) vaccine strategies such as so-called “active” immunotherapy using, e.g., dendritic cell-based, peptide-based, or heat shock–peptide complex vaccines in order to elicit specific immune responses to tumor-specific antigens (TSAs); (2) immune checkpoint blockade by using blocking antibodies against the programmed cell protein 1 (PD-1) (e.g., nivolumab, pembrolizumab, pidilizumab), the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) (e.g., ipilimumab, tremilimumab) or the ligand PD-L1 (atezolizumab) in order to potentiate and refine an active antitumor immune response; (3) adoptive autologous T-cell transfer by using in vitro or ex vivo expanded tumor-infiltrating T lymphocytes which target a TSA; and (4) use of engineered chimeric antigen receptor autologous T cell (CAR T cells) directed against tumor-associated antigens (TAAs) or TSAs by circumvention of major histocompatibility complex (MHC) restriction.
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
An improved understanding of DLBCL biology and role of tumour microenvironment continues to provide a platform for immunotherapy and chemoimmunotherapy strategies for patients with relapsed and chemoimmunotherapy refractory disease. Immune checkpoint inhibitors, initially pidilizumab, ipilimumab and nivolumab, have also been tested and modest efficacy observed so far. Other approaches, both as monotherapy and combinations, include BCR inhibitors (such as ibrutinib), BCL2 inhibitors (in particular venetoclax [ABT-199]) and immunomodulatory agents (in particular lenalidomide). Efficacy and safety of novel CD20 monoclonal antibodies are being compared to rituximab in combination with chemotherapy and novel targeted agents. Efforts are also assessing the targeting of the JNK pathway with novel JNK inhibitors in the ABC-subtype. Another candidate prognostic marker and possible therapeutic target is UCH-L1, a multifunctional molecule of the ubiquitin C-terminal hydrolase L1. It has been hypothesized that UCH-L1 alters gene expression and antigen-specific immunity particularly in GCB cells, possibly through its interactions with BCL6. Significantly higher levels of UCH-L1 have been noted in the GCB-subtype compared to the ABC-subtype and predict poor outcomes. In this regard, the activity in murine models of a UCH-L1 inhibitor, LDN-57444, is interesting. There is also much interest in dual inhibition of oncogenic targets and efforts to improve ‘precision immunology’ approaches, for example, by combining CAR T-cell therapy with other agents, such as BTK inhibitors and immune checkpoint inhibitors. A combination of PI3Kδ inhibitor, INCB040093 and a JAK1 inhibitor, itacitinib, has also demonstrated activity in relapsed/refractory patients with DLBCL and also other subtypes of lymphoma. This latter study is also an interesting example of the use of a second agent (in the combination) to enhance the efficacy and also decrease the toxicity, in this case itacitinib reduced the hepatotoxicity associated with INCB040093.
Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled
Published in Expert Review of Anticancer Therapy, 2019
Jan Philipp Bewersdorf, Maximilian Stahl, Amer M. Zeidan
After mouse models showed that an increased PD-1/PD-L1 expression led to a state of T-cell exhaustion which could be overcome by ICB [56], several monoclonal antibodies targeting PD-1/PD-L1 signaling have been developed and tested in AML patients. Pidilizumab (CT-011) was one of the first monoclonal anti-PD-1 antibodies to be tested in hematologic malignancies. In a phase I study of 17 patients with advanced hematologic neoplasms (eight AML, one MDS) treated with a single dose of pidilizumab, only one AML patient achieved a reduction in bone marrow blast count but progressed subsequently [57]. Other anti-PD-1 antibodies that are currently being studied as monotherapy for AML or MDS at various disease stages include nivolumab and pembrolizumab (Table 1). In the KEYNOTE-013 trial (NCT01953692), 28 MDS patients who progressed on therapy with HMAs and were treated with pembrolizumab achieved an overall response rate of only 4% (1 partial remission) with hematologic improvement in 11% of patients [58].
Checkpoint inhibitors and acute myelogenous leukemia: promises and challenges
Published in Expert Review of Hematology, 2018
Mansour Alfayez, Gautam Borthakur
There are number of ongoing trials in the setting of SCT. NCT02846376 is a trial examining nivolumab and ipilimumab effect in a population that is at high risk for posttransplant relapse; NCT01822509 and NCT03286114 are examining the effect of ipilimumab and pembrolizumab, respectively, in the setting of posttransplant relapse. NCT02771197 is looking for the effect of pembrolizumab in autologous SCT for those who are not eligible for allo-SCT transplant. One reported trial in the setting of SCT (NCT00060372) with ipilimumab in 12 patients with relapsed AML and 4 others with relapsed extramedullary disease, 3 patients with leukemia cutis, and 1 with myeloid sarcoma went into remission. In this trial, ASH 2017 update reported 2 of the 3 patients with leukemia cutis remained in CR at 30 and 32 months of follow-up [107]. This suggests a particular benefit in patients who relapsed with extramedullary disease [103] even though the mechanism is unclear. As been discussed before, in a murine model, blocking PD-1 resulted into accelerated GVHD that was further augmented by blocking CTLA-4 [73]. However, in another study, CTLA-4 alone was more selective in augmenting GVL [74]. As reported above, GVHD remains a concern with CTLA-4 blockade. Pidilizumab was also tested in phase 1 trial with four patients with post-allo-SCT relapse with no exciting results [102]. One patient experienced grade 4 gastrointestinal GVHD and died with persistent AML and GVHD, and it was not clear if GVHD was related to pidilizumab [102].
Emerging PD-1/PD-L1 antagonists for the treatment of malignant melanoma
Published in Expert Opinion on Emerging Drugs, 2021
Vito Vanella, Lucia Festino, Maria Grazia Vitale, Benedetta Alfano, Paolo Antonio Ascierto
Pidilizumab (CT-011), is a humanized anti-PD-1 antibody studied in aggressive and indolent lymphomas showing clinical activity correlated with PD-1/PD-L1-positive lymphocytes. A phase 2 multicenter, open-label, randomized study to evaluate the safety and efficacy of pidilizumab in patients with metastatic melanoma is underway. Despite low response rates, the 12-month survival rate seems to be comparable to that of other anti-PD-1 antibodies. The toxicity profile was manageable [43]. Developed by Medivation