Mechanisms of and approaches to overcoming resistance to immunotherapy.

Mechanisms of and approaches to overcoming resistance to immunotherapy. Hematology Am Soc Hematol Educ Program. 2019 Dec 06;2019(1):226-232 Authors: Schultz L, Gardner R Abstract Immunotherapies have been successfully developed for the treatment of B-cell acute lymphoblastic leukemia (B-ALL) with FDA approval of blinatumomab, inotuzumab, and tisagenlecleucel for relapsed or refractory patients. These agents target either CD19 or CD22, which are both expressed on the surface of the leukemic blasts in the majority of patients. The use of these agents has greatly transformed the landscape of available treatment, and it has provided curative therapy in some patients. As the field has matured, we are learning that for most patients, the currently available immunotherapies are not curative. Leukemic resistance to both CD19 and CD22 pressure has been described and is a major component of developed resistance to these therapies. Patients with B-ALL have developed CD19- or CD22-negative B-ALL, and in more rare cases, they have undergone lineage switch to acute myeloid leukemia. Current efforts are focusing on overcoming antigen escape, either by forced antigen expression or by dual-targeting therapies. A functional immune system is also required for maximal benefit of immunotherapy, particularly with chimeric antigen receptor (CAR) T-cell therapies. Data are now being produced that may allow for the prospective identification of patients whose immune deficits may ...
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research

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This article reviews the current landscape of antibody-based and cellular immunotherapies under current clinical evaluation with an emphasis on active or soon-to-open phase 1 trials for children with relapsed/refractory AML. PMID: 31808843 [PubMed - in process]
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are emerging as an effective treatment for patients with chemotherapy refractory hematological malignancies. Indeed, the use of unselected donor lymphocyte infusions has demonstrated successes in treating patients with AML and T-lineage leukemia post–allogeneic transplantation. The development of ex vivo manipulation techniques such as genetic modification or selection and expansion of individual cellular components has permitted the clinical translation of...
Source: The Cancer Journal - Category: Cancer & Oncology Tags: Review Articles Source Type: research
Abstract Refractory and relapsed acute myeloid leukemia (AML) and T-lineage leukemia have poor prognosis and limited therapeutic options. Adoptive cellular immunotherapies are emerging as an effective treatment for patients with chemotherapy refractory hematological malignancies. Indeed, the use of unselected donor lymphocyte infusions has demonstrated successes in treating patients with AML and T-lineage leukemia post-allogeneic transplantation. The development of ex vivo manipulation techniques such as genetic modification or selection and expansion of individual cellular components has permitted the clinical tr...
Source: Cancer Journal - Category: Cancer & Oncology Authors: Tags: Cancer J Source Type: research
Conclusions Several model systems are now available to characterize the MSC-tumour interplay in the TME. These offer early promise in establishing robust preclinical platforms for the identification of crucial molecular pathways and for the assessment of clinical efficacy of novel drugs to inhibit cancer development and progression. However, selection of the right model for a given study should be shaped on the purpose, and should also consider fixed biological, biochemical, and biophysical parameters according to the specific tumour type. Finally, in order to get reliable and useful results to be translated to the clinic...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions: CAR T cell therapies have demonstrated the clinical benefits of harnessing our body's own defenses to combat tumor cells. Similar research is being conducted on lesser known modifications and gene-modified immune cells, which we highlight in this review. Introduction Chimeric antigen receptors and engineered T cell receptors (based on previously identified high affinity T cell receptors) function by redirecting T cells to a predefined tumor-specific (or tumor-associated) target. Most of these modifications use retroviral or lentiviral vectors to integrate the construct, and most of the receptors ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusions: HyperCVAD results in high remission rates in patients with ALAL, with low incidence of early mortality and high ability to proceed to allogeneic transplantation following response. HyperCVAD can be considered an effective front-line therapy for patients with ALAL. Additionally, hyperCVAD may be a backbone for incorporation of novel immunotherapies and targeted therapies, which may improve results in patients with appropriate targets.DisclosuresSweet: Astellas: Consultancy; Agios: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bu...
Source: Blood - Category: Hematology Authors: Tags: 612. Acute Lymphoblastic Leukemia: Clinical Studies: Poster II Source Type: research
ConclusionOur first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total bod...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Immunotherapy Source Type: research
Background: FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein uniformly expressed on leukemic blasts in acute myeloid leukemia (AML), and driver of leukemia-genesis in FLT3-ITD+ (Internal tandem duplication) AML. There is an increasing body of pre-clinical and clinical data suggesting that FLT3-ITD+ AML blasts respond to FLT3 inhibitor treatment by augmenting FLT3 expression in order to sustain the survival signal provided by this mutation. Here, we analyzed FLT3 expression on FLT3 wild type and FLT3-ITD+ AML cells after treatment with the FLT3 inhibitors midostaurin, quizartinib and crenolanib, and determined t...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Immunotherapy Source Type: research
The objectives of this ongoing study are to evaluate the safety, pharmacokinetics, and pharmacodynamics of AMG 330 in R/R AML and to estimate the maximum tolerated dose.Methods: This was a phase 1 dose escalation study evaluating AMG 330 as a continuous IV infusion in patients with R/R AML, with single-patient cohorts for the first 3 doses and subsequently 3-6 patients per cohort (NCT#02520427). Response was per revised IWG criteria with the addition of complete response (CR) with partial hematologic recovery. After completing the first cycle without dose-limiting toxicity (DLT), up to 5 additional cycles could be given fo...
Source: Blood - Category: Hematology Authors: Tags: 613. Acute Myeloid Leukemia: Clinical Studies: Immunotherapy and New Agents Source Type: research
CONCLUSIONS: Objective responses (CR and CRis) were seen in one third of relapsed/refractory AML patients during the initial stages of dose escalation in this first-in-human clinical trial with IMGN632, a novel CD123-targeting ADC. No dose limiting toxicities have been observed, and PK and PD data support continued dose escalation, which is ongoing.Figure 1. A. Maximum percent changes in bone marrow blasts from baseline. Patients who achieved an objective response (CR or CRi) are shown in gray. B. CD123 receptor saturation. Average saturation curves for the first four cohorts are presented.DisclosuresDaver: Karyopharm: Res...
Source: Blood - Category: Hematology Authors: Tags: 613. Acute Myeloid Leukemia: Clinical Studies: Immunotherapy and New Agents Source Type: research
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