Clinical investigation of CAR T cells for solid tumors: lessons learned and future directions

Publication date: Available online 16 October 2019Source: Pharmacology &TherapeuticsAuthor(s): Stephen J. Bagley, Donald M. O’RourkeAbstractChimeric antigen receptor (CAR) T cells are a form of autologous immunotherapy that has changed the therapeutic landscape of hematologic malignancies. CAR T cell therapy involves collection of a patient’s T cells by apheresis, ex vivo genetic modification of the T cells to encode a synthetic receptor that binds a specific tumor antigen, and infusion of the T cells back into the patient. With the unprecedented success of CAR T cells in leukemia and lymphoma, a growing number of preclinical studies and clinical trials have focused on translating this treatment to solid tumors. In non-hematologic malignancies, however, response rates have been much less favorable. Some of the most significant challenges for CAR T cell immunotherapy in solid cancers include a paucity of unique tumor target antigens, limited CAR T cell trafficking to tumor sites, tumor heterogeneity and antigen loss, and the severely immunosuppressive tumor microenvironment. This review article provides an update on completed and ongoing clinical trials of CAR T cells for solid tumors, as well as an overview of strategies to improve CAR T cell efficacy in non-hematologic malignancies.
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research

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We examined publication bias and excess significance bias. 63 articles corresponding to 247 meta-analyses were eligible. Nine meta-analyses were classified to have convincing evidence, and 75 were classified as suggestive evidence. The clinical benefit of immunotherapy was supported by convincing evidence in the following settings: anti-PD-1/PD-L1 monoclonal antibody (mAb) therapy for treating advanced melanoma and non-small cell lung cancer (NSCLC), the combination of rituximab and chemotherapy for treating chronic lymphocytic leukemia and B-cell non-Hodgkin’s lymphoma, adoptive cell immunotherapy for NSCLC, and...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Yicheng Ni Cancer remains a major cause of death globally. Given its relapsing and fatal features, curing cancer seems to be something hardly possible for the majority of patients. In view of the development in cancer therapies, this article summarizes currently available cancer therapeutics and cure potential by cancer type and stage at diagnosis, based on literature and database reviews. Currently common cancer therapeutics include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, treatment with curative intent by these methods are mainly eligible for patients with localized diseas...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Abstract Adoptive immunotherapy of cancer using T cells expressing chimeric antigen receptors (CARs) is now an approved treatment for non-Hodgkin lymphoma (NHL) and B cell acute lymphoblastic leukemia (B-ALL), inducing high response rates in patients. The infusion products are generated by using retro- or lentiviral transduction to induce CAR expression in T cells followed by an in vitro expansion protocol. However, use of viral vectors is cumbersome and is associated with increased costs due to the required high titers, replication-competent retrovirus (RCR) detection and production/use in a biosafety level 2 cul...
Source: Mol Biol Cell - Category: Molecular Biology Authors: Tags: Methods Mol Biol Source Type: research
We describe three clinical scenarios in which CAR T- cell immunotherapy interfered with HIV-1 testing including: (1) routine infectious disease screening prior to stem cell transplantation in a 16-year-old female with B-cell acute lymphoblastic leukemia, status post CAR T- cell treatment (2) routine infectious disease screening prior to 2nd CAR T- cell collection in a 65-year-old male with diffuse large B-cell lymphoma who failed initial CAR T- cell treatment and (3) routine infectious risk assessment following an occupational health exposure from a 58 -year-old male with multiple myeloma, status post CAR T- cell treatment...
Source: Clinical Lymphoma and Myeloma - Category: Cancer & Oncology Authors: Tags: J Clin Microbiol Source Type: research
Publication date: Available online 18 October 2019Source: Best Practice &Research Clinical HaematologyAuthor(s): Mathew L. Cooper, John F. DiPersioAbstractAt present, the only curative therapy for patients with T-cell malignancies is allogeneic stem cell transplant, which has associated risks and toxicities. Novel agents have been tried in relapsed T-cell acute lymphoblastic leukemia (T-ALL), but only one, with 20%-30% complete remission rates, has been approved by the US Food and Drug Administration. T-ALL is a heterogeneous disease, but it has universal overexpression of CD7 as well as several other T-cell markers, s...
Source: Best Practice and Research Clinical Haematology - Category: Hematology Source Type: research
Authors: Mohanty R, Chowdhury CR, Arega S, Sen P, Ganguly P, Ganguly N Abstract Cancer has recently been identified as the leading cause of mortality worldwide. Several conventional treatments and cytotoxic immunotherapies have been developed and made available to the market. Considering the complex behavior of tumors and the involvement of numerous genetic and cellular factors involved in tumorigenesis and metastasis, there is a need to develop a promising immunotherapy that targets tumors at both the cellular and genetic levels. Chimeric antigen receptor (CAR) T cell therapy has emerged as a novel therapeuti...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
Non-genetic cellular plasticity has recently emerged as a basis for therapeutic resistance in cancer. Therefore, a better understanding of cellular plasticity and adaptive state changes in myeloma cells and the immune microenvironment is critical to develop effective therapeutic approaches that can overcome drug resistance. We performed fluorescence activated cell sorting and full-length single-cell RNA sequencing of myeloma cells and CD45+ immune cells from the bone marrow of 8 patients with relapsed/refractory multiple myeloma (RRMM) treated on a clinical trial with elotuzumab, pomalidomide, bortezomib and dexamethasone ...
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
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Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
Immunotherapy has achieved unprecedent long-term survival rates in solid tumors and has begun to transform myeloma (MM) treatment as well. Among strategies to enhance cancer cell immunogenicity, induction of immunogenic cell death (ICD) is particularly promising: the release of danger signals from dying cancer cells may, indeed, stimulate a specific anti-cancer immunity via T-cell priming by dendritic cells (DCs). Here, we sought to investigate the molecular basis and clinical relevance of bortezomib (BTZ)-induced ICD in MM.
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
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Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
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