Autologous graft versus myeloma: it’s not a myth

Dong, Shuai; Ghobrial, Irène M.

doi:10.1172/jci125431

Cited by 5 publications

(3 citation statements)

References 14 publications

(15 reference statements)

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“…While the primary effect of auto-HCT has been attributed to cytoreductive chemotherapy, human observational studies and preclinical experimental data also implicate a degree of immune control of myeloma in autograft recipients. 45,46 In a mouse model of auto-HCT, CD8 + T cells in the donor graft conferred immune control of myeloma in an IFN-dependent-fashion. 47 Adoptive cell therapy in a syngeneic mouse model may partly depend on signals from the intestinal microbiota crossing an impaired gut barrier to augment anti-tumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study

Khan¹,

Lindner

Gomes

et al. 2021

Blood

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We have previously described clinically relevant reductions in fecal microbiota diversity of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1,161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma and amyloidosis in an observational study conducted at two transplant centers in the United States. Using 16S ribosomal gene sequencing, we assessed fecal microbiota diversity as measured by the inverse Simpson index, and composition. At both centers, early pre-transplant fecal microbiota diversity was lower than in healthy control subjects and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to allo-HCT. Above-median fecal intestinal diversity in the peri-engraftment period was associated with decreased risk of death or progression (PFS HR 0.46 [95% CI, 0.26-0.82], P=0.008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and post-transplant outcomes should be undertaken.

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Section: Discussionmentioning

confidence: 99%

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study

Khan¹,

Lindner

Gomes

et al. 2021

Blood

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“…2 T TE cells, which mediate antimyeloma responses in NDMM patients, can be affected by the accumulation of noncytotoxic CD69 1 T TE cells within MILs. Tracing CD69 1 T TE cells within MILs and correlating their numbers with clinical outcome in MM patients receiving MILs as adoptive T-cell therapy33,34 could provide essential insights into role of BM-CD69 1 T TE cells in antimyeloma immunity.…”

mentioning

confidence: 99%

Inverse relationship between oligoclonal expanded CD69− TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients

et al. 2020

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CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69− and CD69+ subsets, while only CD69− cells are found in PB. Within the BM-TTE compartment, CD69− and CD69+ cells are found in comparable proportions in controls, while CD69− cells are dominant in MGUS and SMM and predominantly either CD69− or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69−TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69−TTE cells include multiple oligoclonal expansions of T-cell receptor/Vβ families shared between BM and PB of NDMM. Oligoclonal expanded CD69−TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69−TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69−TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69− and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease.

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“…Regulatory CD4 + T cells (Treg) and cytotoxic CD8 + T cells have emerged as the dominant effectors in host myeloma control in syngeneic transplantable murine myeloma models ( 2 , 3 ) underpinning autologous graft versus myeloma as an important process in disease control ( 4 ). The dramatic success of Chimeric Antigen Receptor (CAR) T cell therapies in myeloma reinforces the vulnerability of the malignant plasma cell to T cell-mediated cytotoxicity, even though the durability of response remains an issue ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

et al. 2021

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The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients.

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Autologous graft versus myeloma: it’s not a myth

Cited by 5 publications

References 14 publications

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study

Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study

Inverse relationship between oligoclonal expanded CD69− TTE and CD69+ TTE cells in bone marrow of multiple myeloma patients

Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

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