How to Train your T cells: Overcoming Immune Dysfunction in Multiple Myeloma.

How to Train your T cells: Overcoming Immune Dysfunction in Multiple Myeloma. Clin Cancer Res. 2019 Oct 31;: Authors: Cohen AD, Raje N, Fowler JA, Mezzi K, Scott EC, Dhodapkar MV Abstract The progression of multiple myeloma (MM), a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in MM have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in MM, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell-dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell-associated changes during the evolution of MM and provides an overview of T-cell-dependent immuno-oncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the MM disease continuum; treatment modalities that redirect patient T cells to elicit an anti-MM response, namely chimeric antigen receptor (CAR) T cells and bispecific antibodies (including BiT...
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research

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RARITAN, NJ, February 10, 2020 – The Janssen Pharmaceutical Companies of Johnson &Johnson announced today the submission of a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) seeking approval of DARZALEX® (daratumumab) in combination with Kyprolis® (carfilzomib) and dexamethasone (DKd) for relapsed/refractory multiple myeloma. The sBLA is supported by results from the Phase 3 CANDOR study, which compared treatment with DKd to carfilzomib and dexamethasone (Kd) in patients with multiple myeloma who relapsed after one to three prior lines of therapy. “Wh...
Source: Johnson and Johnson - Category: Pharmaceuticals Tags: Innovation Source Type: news
Inokuchi Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM p...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
ConclusionMyeloma has the ability to demonstrate a response to pneumococcal vaccine, independently of preexisting hypogammaglobulinemia and possibly of treatment ‐induced immunodepression. We also observed a drop in the serum response overtime and following autologous transplantation. Further studies in larger sample are needed to understand the benefit of vaccination strategies in these patients.
Source: Cancer Medicine - Category: Cancer & Oncology Authors: Tags: ORIGINAL RESEARCH Source Type: research
Hui Zhou, Xiaoyan Fu, Qian Li and Ting Niu* Department of Hematology and Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu, China Background: Immune checkpoint inhibition therapy with monoclonal antibody against programmed cell death protein 1 (PD-1), including nivolumab and pembrolizumab, has demonstrated powerful clinical efficacy in the treatment of advanced cancers. However, there is no evidence-based systematic review on the safety and efficacy of anti-PD-1 antibody in treating lymphoma. Methods: To evaluate the safety and efficacy of nivolumab/pembrolizumab, we analyzed clin...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Conclusions The major challenges in the development of adoptive cell therapy for T cell tumors, as mentioned above, remain fratricide, T cell aplasia and the potential for leukemic transduction or poor T cell function if used in the autologous setting. Approaches to overcome fratricide include the genetic modification and deletion of the T cell antigen in the case of long-term CAR-T cell persistence or regulated CAR-T expression. To ensure restoration of T cell immunity, transient CAR expression can be achieved incorporation of a CAR suicide gene, transient CAR expression using mRNA electroporation, or short-lived NK cell...
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: As T-cell responses can only be raised in a subfraction of patients despite antigen expression, and the number of responses increases with more antigens used, vaccination strategies should assess patients' antigen expression and use a "cocktail" of peptide vaccines. PMID: 27533084 [PubMed - as supplied by publisher]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
MAGE-A3 is an immunogenic tumor-associated antigen expressed in multiple myeloma (MM) patients and conferring poor prognosis, making it a rational target for immunotherapy. Recombinant MAGE-A3 protein was administered in AS15 immunostimulant (containing MPL, QS-21, and CpG 7909) to 13 MM patients pre- and post-autologous stem cell transplant (ASCT) coupled with infusion of vaccine-primed autologous peripheral blood lymphocytes (PBL) early post-ASCT (NCT01380145). All patients had MAGE-A+ myeloma cells at baseline and had an acceptable safety profile during immunotherapy.Robust antibody responses against MAGE-A3 (assessed b...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Clinical Research (Excluding Clinical Trials) Source Type: research
We report on the safety and immunogenicity of idiotypic DNA vaccination in a phase I, non-randomised, open-label study in patients with multiple myeloma. The study used DNA fusion gene vaccines encoding patient-specific single chain variable fragment, or idiotype (Id), linked to fragment C (FrC) of tetanus toxin. Patients in complete or partial response following high-dose chemotherapy and autologous stem cell transplant were vaccinated intramuscularly with 1 mg DNA on six occasions, beginning at least 6 months post-transplant; follow-up was to week 52. Fourteen patients were enrolled on study and completed vacci...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Conditions:   Refractory Multiple Myeloma;   Stage I Multiple Myeloma;   Stage II Multiple Myeloma;   Stage III Multiple MyelomaInterventions:   Biological: autologous immunoglobulin idiotype-KLH conjugate vaccine;   Biological: sargramostim;   Biological: aldesleukin;   Other: laboratory biomarker analysisSponsors:   Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium;   National Cancer Institute (NCI)Active, not recruiting - verified May 2015
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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