Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy

Abstract

• CD19-targeted T-cell immunotherapy reveals that a population of PCs lacking CD19 expression survives long-term, independent of B cells.• Preexisting humoral immunity to vaccine-related antigens can persist in patients despite marked B-cell aplasia after CTL019 immunotherapy.The mechanisms underlying the maintenance of long-lasting humoral immunity are not well understood. Studies in mice indicate that plasma cells (PCs) can survive up to a lifetime, even in the absence of regeneration by B cells, implying the presence of longlived PCs as a mechanism for long-lasting immunity. Evidence from humans treated with anti-CD20, which depletes circulating B cells, also suggests B-cell-independent longterm survival of some PCs. On the other hand, antibody responses may be sustained solely by short-lived PCs with repopulation from clonally related memory B cells. To explore PC longevity and humoral immunity in humans, we investigated the fate of PCs and their antibodies in adult and pediatric patients who received chimeric antigen receptor-based adoptive T-cell immunotherapy targeting CD19 to treat B-cell lineage malignancies (CTL019). Treatment with CTL019 is frequently associated with B-cell aplasia that can persist for years. Serum antibody titers to vaccine-related antigens were measured, and quantitative assessment of B cells and PCs in blood and bone marrow was performed at various time points before and after CTL019 therapy. While total serum immunoglobulin concentrations decline following CTL019-induced B-cell aplasia, several vaccine/pathogen-specific serum immunoglobulin G and A (IgG and IgA) titers remain relatively stable for at least 6 and 12 months posttreatment, respectively. Analysis of bone marrow biopsies after CTL019 revealed 8 patients with persistence of antibody-secreting PCs at least 25 months post-CTL019 infusion despite absence of CD19 1 CD20 1 B cells. These results provide strong evidence for the existence of memory B-cell-independent, long-lived PCs in humans that contribute to long-lasting humoral immunity. (Blood. 2016;128(3):360-370)

Donor origin CAR T cells: graft versus malignancy effect without GVHD, a systematic review

“…Due to dose escalation trial design of many studies, heterogeneity of patient population and various settings (prophylaxis vs salvage) in which CAR T cells were used, it was not possible to summarize disease response about individual patients or subset of disease types. The longest duration of CR reported in the trial was 30 months in a patient of CLL [21]. Only five out of 72 patients developed GVHD (6.9%).…”

“…The circulating pool of CD 19 targeted immunity CAR T cells persist for longer duration, and achieve durable remission. Treatment-related complications are due to so-called 'on-target' and 'on-target/off-tumor' effects, such as cytokine releases syndrome, tumor lysis syndrome, long term B-cell aplasia, hypo-gammaglobulinemia and a spectrum of CNS-related side effects [21]. Post Allo-HSCT relapses data from pediatric and adult trials show dismal prognosis, even patients undergoing a second transplant have poor prognosis [25].…”

The efficacy of anti-CD19 chimeric antigen receptor T cells for B-cell malignancies

“…Eleven clinical trials reported CR and PR [28,30,35,36,39,42,43,45,51,52,54], in addition another 27 clinical trials reported CRe and PRe [17À29, 31,32À34,37,38,40,41,44,46À50,53]. In two clinical trials, only remission was reported [17,22], and we calculated them as CRe and PRe.…”

Remote Controlled CARs: Towards a Safer Therapy for Leukemia

“…Therefore, B-cell aplasia is one consequence of constitutive CAR T cells that target CD19. In adults, acquired B-cell aplasia has been well tolerated, because humoral immunity is maintained by long-lived plasma cells that do not express CD19 (1). However, in children, B-cell aplasia may present an increased risk of infection because many children have not yet established immunologic memory, and it is not possible to vaccinate children with B-cell aplasia.…”