Sequential allogeneic and autologous CAR-T–cell therapy to treat an immune-compromised leukemic patient

Abstract

Key Points CAR-T–cell therapy normally requires the patient’s own healthy T cells. An allogeneic CAR-T bridging therapy could rescue lymphopenic patients.

HLA-matched and HLA-haploidentical allogeneic CD19-directed chimeric antigen receptor T-cell infusions are feasible in relapsed or refractory B-cell acute lymphoblastic leukemia before hematopoietic stem cell transplantation

“…Two case reports have shown that the use of HCART19 cells as part of a conditioning regimen for allo-HSCT has beneficial therapeutic effects [6,7]. In another case involving the HCART19 cells, no myeloablative conditioning regimen was used, and the patient had a mild response to treatment, which is consistent with the responses we observed [5]. Several reports have found that B-ALL relapses after treatment with autologous CAR-T cells.…”

“…Patient 6 exhibited subcutaneous tissue infiltration in the right upper limb, and the infiltrating lesion was alleviated after HCART19 cell infusion. Three cases have been reported to have received HCART19 cells before allo-HSCT [5][6][7]. Two case reports have shown that the use of HCART19 cells as part of a conditioning regimen for allo-HSCT has beneficial therapeutic effects [6,7].…”

Genetically engineered T cells for cancer immunotherapy

“…First-generation CAR-T cells, which contain a CAR construct with only CD3ζ in the intracellular domain, showed limited antitumor efficacy in clinical trials 16,256 , mainly due to the lack of costimulatory molecules that are essential for T cell responses to antigens 257,258 . In fact, the intracellular signal transduction domain always includes the indispensable CD3ζ chain, which contains immunoreceptor tyrosine-based activation motifs (ITAMs) that function in signal transduction 259 , and one or more intracellular costimulatory molecules, such as CD28, 4-1BB (CD137), or CD27, to transmit activation signals 180,[260][261][262][263][264][265][266][267][268][269][270] . In terms of the intracellular signal domain, CARs have evolved from the first to the fourth generation.…”

“…Adding CD27 to the second-generation CAR construct increased T cell expansion, BCL-X L upregulation, and IFN-γ production, and the resulting cells showed comparable in vivo efficacy compared with CD28ζ and 4-1BBζ CAR-T cells 308 . In addition, clinical data demonstrated that CD28-CD27-CD3ζ CAR-T cells were safe when infused to treat leukemia 262,308 . The intracellular domain of NKG2D, either individually or in combination with CD28/4-1BB domains, enhanced many properties of CAR-T cells, including the secretion of IFN-γ, TNF-α, and GM-CSF, and improved antitumor efficacy in vivo [309][310][311][312][313] .…”

Achievements and Challenges in Allogeneic Hematopoietic Stem Cell Transplantation in Cytogenetically Unfavorable Acute Leukemias (Literature Review)

“…К настоящему времени стало более очевидным, что подходы к лечению ОЛ с прогностически неблагоприятными кариотипами должны стать не только индивидуализированными, но и максимально щадящими. По-видимому, не последнее место в них должно быть отведено использованию менее повреждающих геном таргетных гипометилирующих препаратов и гистондеацетилирующих агентов, полностью ретиноевой кислоты, ингибиторов контрольных точек и многого другого [61][62][63]. Не менее очевидно и то, что некоторые малоперспективные с точки зрения длительной выживаемости после аллоТГСК больные должны переводиться на поддерживающую паллиативную терапию, причем достаточно рано.…”