Pharmacology researchers develop a novel immunotherapy to treat malignancies. In this therapy, T lymphocytes are harvested from patients with a malignancy and genetically modified to express a chimeric antigen receptor composed of an extracellular antigen recognition domain linked with an intracellular T-cell signaling domain. These modified T cells are expanded ex vivo and then infused back into the patient, where they destroy the cancer cells. In one of the experiments, they modify the chimeric antigen receptor to recognize CD19. Use of this treatment is most likely to have which of the following potential complications?

Question

Pharmacology researchers develop a novel immunotherapy to treat malignancies.  In this therapy, T lymphocytes are harvested from patients with a malignancy and genetically modified to express a chimeric antigen receptor composed of an extracellular antigen recognition domain linked with an intracellular T-cell signaling domain.  These modified T cells are expanded ex vivo and then infused back into the patient, where they destroy the cancer cells.  In one of the experiments, they modify the chimeric antigen receptor to recognize CD19.  Use of this treatment is most likely to have which of the following potential complications?

Quizplus · Accepted Answer

11ec160b_37cf_33d6_9249_2fed00e0c08e_MD0001_00 Leukocyte surface molecules are categorized using cluster of differentiation (CD) nomenclature to assist with immunophenotyping, the differentiation of immune cells based on cell surface features (ie, with flow cytometry). Although some CD molecules are expressed on most immune cells (eg, CD45), others are restricted to a specific population of leukocytes. CD19 is a transmembrane protein unique to B lymphocytes that reduces the cytokine threshold for B-cell activation and proliferation following antigen binding. Because B-cell cancers (eg, acute lymphocytic leukemia, diffuse B-cell lymphoma) often overexpress CD19 to increase replication rate, anti-CD19 immunotherapy has been developed to treat these malignancies. CAR T-cell therapy is a specific type of immunotherapy that involves the following: Extraction and purification of T cells from a patient or donor Genetic modification to form a chimeric antigen receptor (CAR), which combines an extracellular antigen recognition domain for an antigen overexpressed in a tumor with an intracellular stimulatory T-cell signaling domain that promotes T-cell activation/proliferation and tumor-killing activity. Reinfusion of the modified T cells into the patient Binding the modified T-cell to its tumor antigen stimulates the release of inflammatory cytokines and promotes destruction of the cancer cell. The most serious adverse effect is a life-threatening cytokine storm, which must be countered with urgent anti-IL-6 treatment (eg, tocilizumab) to prevent death. In addition, anti-CD19 therapy in particular can also cause hypogammaglobulinemia due to destruction of healthy B cells/plasma cells. (Choice A) Autoimmune endocrinopathy sometimes occurs with immune checkpoint inhibitor therapy, which targets surface molecules (eg, PD-1, CTLA-4) on cytotoxic T cells. CD19 is only expressed on B-cells, not T-cells. (Choice B) Graft versus host disease occurs when allogeneic (non-self) immune cells attack host tissue. It does not occur with autologous immune cells because these cells are drawn from the patient and adequately differentiate self from non-self. (Choice D) Myelofibrosis, a chronic myeloproliferative disorder, is associated with exposure to ionizing radiation and toxic chemicals. However, CAR-T cell therapy is not associated with myelofibrosis. In addition, risk of secondary malignancy after CAR-T cell therapy appears to be low overall. (Choice E) Chemotherapy often causes transient myelosuppression due to destruction of rapidly dividing hematopoietic cells. Anti-CD19 therapy may reduce B-cell populations but does not significantly affect other hematologic cells. Educational objective: Chimeric antigen receptor (CAR) T-cell therapy involves extracting T cells from a patient with malignancy, inserting a CAR gene against a protein overexpressed by the malignancy, and then reinfusing the modified T cells back into the patient. CAR T-cell therapy against CD19 is used to treat B-cell malignancy because CD19 is expressed only by B cells. __________ References: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. (http://www.ncbi.nlm.nih.gov/pubmed/29226797)

Pharmacology Researchers Develop a Novel Immunotherapy to Treat Malignancies