Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.

  title={Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.},
  author={Richard A. Morgan and James C.-H. Yang and Mio Kitano and Mark E. Dudley and Carolyn Laurencot and Steven A. Rosenberg},
  journal={Molecular therapy : the journal of the American Society of Gene Therapy},
  volume={18 4},
  • R. MorganJ. Yang S. Rosenberg
  • Published 1 April 2010
  • Biology, Medicine
  • Molecular therapy : the journal of the American Society of Gene Therapy
In an attempt to treat cancer patients with ERBB2 overexpressing tumors, we developed a chimeric antigen receptor (CAR) based on the widely used humanized monoclonal antibody (mAb) Trastuzumab (Herceptin). An optimized CAR vector containing CD28, 4-1BB, and CD3zeta signaling moieties was assembled in a gamma-retroviral vector and used to transduce autologous peripheral blood lymphocytes (PBLs) from a patient with colon cancer metastatic to the lungs and liver, refractory to multiple standard… 

Case Report of a Fatal Serious Adverse Event Upon Administration of T Cells Transduced With a MART-1-specific T-cell Receptor.

Observations suggest that high levels of inflammatory cytokines alone or in combination with semi-acute heart failure and epileptic seizure may have contributed substantially to the occurrence of the acute and lethal event.

Pilot Trial of Adoptive Transfer of Chimeric Antigen Receptor–transduced T Cells Targeting EGFRvIII in Patients With Glioblastoma

Administration of anti-EGFRvIII CAR-transduced T cells did not demonstrate clinically meaningful effect in patients with glioblastoma multiforme in this phase I pilot trial, and there were no objective responses.

A Novel Target Antigen for the Treatment of Acute Myeloid Leukemia by CAR T Cells.

  • P. BeavisK. SekP. Darcy
  • Biology, Medicine
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2017

CAR T Cell Therapy of Non-hematopoietic Malignancies: Detours on the Road to Clinical Success

The history and status of CAR T cell therapy for solid tumors, potential T cell-intrinsic determinants of response and resistance as well as extrinsic obstacles to the success of this approach for much more prevalent non-hematopoietic malignancies are reviewed.

At The Bedside: Clinical review of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies

A thorough overview of the preclinical and clinical development of CAR T cell therapy is presented that will highlight important areas for the basic researcher to investigate in the laboratory and contribute to this exciting field.

Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia.

This study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo persistence of CAR T cells.

Making Better Chimeric Antigen Receptors for Adoptive T-cell Therapy

Several approaches to increase the feasibility and safety of CAR T cells are currently being explored, including investigation into the mechanisms regulating the persistence ofCAR T cells.

Are all chimeric antigen receptors created equal?

  • Jae H. ParkR. Brentjens
  • Biology, Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2015
The efficacy of autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) in patients with relapsed diffuse large B-cell lymphoma is discussed, and it remains unclear whether any particular second-generation CAR design is superior to the other.

Chimeric Antigen Receptor Therapeutic Strategies: The Future of Glioblastoma Management

The history and advantages of CAR-T cell therapies are reviewed, future directions are discussed, and the leading options for tumor specific surface antigens to target withCAR-T cells are described.

CARs and other T cell therapies for MM: The clinical experience.




Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma.

A first-in-humans pilot study sets the stage for clinical trials employing adoptive transfer in the context of minimal residual disease in children with recurrent/refractory neuroblastoma.

A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer

Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term, and future studies need to employ strategies to extend T cell persistence.

Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.

  • M. MiloneJ. Fish C. June
  • Biology, Medicine
    Molecular therapy : the journal of the American Society of Gene Therapy
  • 2009
It is suggested that incorporation of the CD137 signaling domain in CARs should improve the persistence of CARs in the hematologic malignancies and hence maximize their antitumor activity.

Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells.

The results of a proof-of-concept clinical trial in which patients with relapsed or refractory indolent B-cell lymphoma or mantle cell lymphoma were treated with autologous T cells genetically modified by electroporation with a vector plasmid encoding a CD20-specific chimeric T- cell receptor and neomycin resistance gene show the safety, feasibility, and potential antitumor activity of adoptive T-cell therapy using this approach.

Adoptive transfer of autologous, HER2-specific, cytotoxic T lymphocytes for the treatment of HER2-overexpressing breast cancer

The therapeutic potential for Her2-specific T cells for eliminating disseminated HER2-positive tumor cells is suggested and the combination of T cell-based therapies with strategies targeting the tumor stroma to improve T-cell infiltration into solid tumors is proposed.

Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.

T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate-antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer.

A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity1

PBLs expressing this new version of the 4D5 CAR could not only efficiently lyse the autologous fresh tumor digests, but they could strongly suppress tumor growth in a xenogenic mouse model.

Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains

Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance in the context of poorly immunogenic tumors.

A Phase I Study of Interleukin 12 with Trastuzumab in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressing Malignancies

The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment and should be further explored in the context of a larger clinical trial.

Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2.

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC), but phenotypic and functional analysis of circulating mononuclear cells in 18 patients extended this study to identify factors affecting ADCC intensity and variability.