scholarly journals Expression of PD-1 and TIM-3 inhibitory checkpoint molecules by T-lymphocytes in early post-transplant period in multiple myeloma patients

2021 ◽  
Vol 66 (4) ◽  
pp. 499-511
Author(s):  
E. V. Batorov ◽  
V. V. Sergeevicheva ◽  
T. A. Aristova ◽  
S. A. Sizikova ◽  
G. Y. Ushakova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Functional Properties ◽  
Functional Activity ◽  
Interferon Γ ◽  
High Dose ◽  
Proliferative Potential ◽  
Ki 67 ◽  
Hematopoietic Stem ◽  
Post Transplant

Introduction. High-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (auto-HSCT) is the standard of treatment for multiple myeloma (MM) patients. The post-transplant period appears to be promising for targeted anti-checkpoint therapy in MM.Aim — to study the dynamics and functional properties of T-cells expressing inhibitory checkpoint molecules PD-1 and TIM-3 in patients with MM under conditions of lymphopenia after HDC with auto-HSCT.Methods. The study included 40 patients with MM who underwent HDC with auto-HSCT. The counts of PD-1- and TIM3-positive CD8+ and CD4+ T-cells and their functional activity on the intracellular expression of Ki-67, production of granzyme B, and interferon-γ were assessed by fl ow cytometry.Results. Relative counts of patient PD-1+ and TIM-3+ subsets of CD8+ and CD4+ T-cells obtained from bone marrow samples were higher compared to peripheral blood. CD8+ PD-1+ and CD4+ PD-1+ T-cells of MM patients had a pronounced cytotoxic and cytokine-producing potential. The functional activity of CD8+ TIM-3+ and CD4+ TIM-3+ T-cells was signifi cantly reduced compared with TIM-3-negative subsets. Low functional activity was also detected in populations of CD8+ and CD4+ T-lympho cytes, co-expressing PD-1 and TIM-3. The frequencies of T-cells expressing PD-1 and TIM-3 increased signifi cantly on the engraftment day after auto-HSCT. The proliferative activity of PD-1+ and TIM-3+ CD4+ and CD8+ T-cells and the cytotoxic potential of PD-1+ and TIM-3+ CD8+ T-cells were also signifi cantly increased compared to the data prior auto-HSCT.Conclusions. PD-1-positive T-cells in MM patients are related to activated or “early dysfunctional” but not exhausted subsets, while T-cells exhaustion is more analogous with CD8+ TIM-3+ and CD4+ TIM-3+ T-cells, as well as with subsets co-expressing PD-1 and TIM-3. To identify the state of T-cells exhaustion, it is necessary to evaluate T-cells subsets co-expressing PD-1, TIM-3, and other ICMs, and/or to study their functional properties. In the early post-transplant period, the proportion of Tcells expressing PD-1 and TIM-3 increases due to an increase in their proliferative potential.

The Influence of Migration, Alloreactive Repertoire and Memory Subset on the Differential Ability of Naive and Memory T Cells To Induce GVHD.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 577-577 ◽  
Author(s):  
Britt E. Anderson ◽  
Warren D. Shlomchik ◽  
Mark J. Shlomchik
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Functional Properties ◽  
Chronic Gvhd ◽  
Effector Memory ◽  
Proliferative Potential ◽  
M Cells ◽  
Hematopoietic Stem ◽  
Memory Phenotype ◽  
Effector Functions

Abstract Allogeneic stem cell transplantation (alloSCT) can cure many hematologic malignancies and hematopoietic stem cell disorders but is frequently complicated by graft vs. host disease (GVHD). We and others have published that memory phenotype (CD62LloCD44hi) T cells do not cause GVHD but can engraft and mount immune responses, including graft-vs.-tumor (GVT) effects. Importantly, these findings apply to GVHD induced by CD4 or CD8 T cells, and across major MHC differences. Thus, the inability to induce GVHD seems a fundamental property of memory phenotype (M) cells. We are investigating several hypotheses to explain why naïve cells (N) cause potent GVHD but M cells do not, including: 1. M cells lack CD62L and fail to traffic to LN and PP, two sites that may be essential for initial priming to allogeneic antigens and 2. M cells have a restricted alloreactive repertoire. There are at least two types of memory cells: central memory (CM) and effector memory (EM). EM cells (CD62LloCCR7neg) quickly express effector functions upon restimulation, preferentially migrate to tissues and spleen (bypassing LNs) and have relatively lower proliferative potential. CM cells (CD62LhiCCR7pos) have hybrid properties of both N and effector cells. Like N cells, their adhesion and chemokine receptors promote migration to LNs; however, their effector functions are more vigorous than N cells, yet slower than EM cells. It is of clinical interest for the design of M cell transfusion to determine the contributions of CM vs. EM cells in GVHD, but prior studies have not clearly investigated CM cells. We therefore compared GVHD initiated by N, EM and CM CD4 cells in the B6 (H-2b) ->BALB/c (H-2d) model. CM cells caused severe GVHD, similar to that induced by N cells. This suggests that LN homing enables M cells to initiate GVHD and/or that CM cells have unique functional properties required to initiate GVHD which are lacking in EM cells. We next asked whether LN entry was required for donor cells to initiate GVHD. N cells induced GVHD, albeit less severe than in WT recipients, in recipients lacking all secondary lymphoid organs (LN, PP and spleen), suggesting that priming in tissues is sufficient. Both of these findings support those of Beilhack, et al. (Blood2005;106:1113) that migration affects T cell initiation of GVHD. However, we also found that N cells from CD62L-deficient donors caused GVHD. Thus, because CD62L function and even secondary lymphoid tissue are dispensable for GVHD induction, we conclude that homing differences alone do not control GVHD and that critical functional properties other than homing must limit EM cells’ ability to induce GVHD. To address the role of repertoire, we increased the alloreactive precursor frequency of M cells. We isolated Thy1.1 (B6.C) (H-2d) effector T cells from mice with active GVHD (BALB/c recipients), and therefore with expanded anti-BALB/c repertoire, and parked them in syngeneic RAG1-/- (B6.C) recipients to allow them to differentiate into M cells. After 4 weeks we re-isolated the alloreactive M cells and transplanted them into new BALB/c recipients. The alloreactive M cells engrafted and caused transient skin GVHD without gut GVHD, unlike the more severe chronic GVHD induced by fresh N cells. This muted GVHD argues that although M cells can cause limited GVHD if their repertoire is artificially increased, they are still lacking in other functional properties required for optimal GVHD induction.

Chimerism Induction Without GVHD Following Low Intensity Conditioning In MHC Disparate Recipients: Combining The Benefit Of Cyclophosphamide Post Transplant With The Tolerogenicity Of Megadose T Cell Depleted HSCT

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3238-3238
Author(s):  
Esther Bachar-Lustig ◽  
Noga Or-Geva ◽  
Yael Zlotnikov Klionsky ◽  
Yair Reisner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Transplantation ◽  
High Dose ◽  
Chimeric Mice ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Low Intensity ◽  
Significant Difference ◽  
Donor Type

Abstract Achieving allogeneic T-cell depleted BM (TDBM) engraftment under non-myeloablative conditioning represents a potentially safe and attractive approach for generating tolerance as a platform for organ transplantation and for the treatment of non-malignant diseases. However, overcoming the abundant host anti-donor T-cells (HADTC) surviving such protocols remains a major challenge. The potential role of megadose T cell depleted BM transplants in overcoming this barrier was shown when using 6.0Gy sublethal TBI, but chimerism could not be attained upon further reduction of the conditioning. An alternative approach currently in clinical use is based on the administration of high dose cyclophosphamide at days 3-4 after transplantation. However, attempts have been limited to T cell replete transplants containing at least 2x106 T cells/Kg. The latter are clearly critical for achieving engraftment of mis-matched transplants but they are also associated with a significant risk for GVHD. In the present study, we evaluated the potential benefit of combining these two approaches. Initially, regular (5x106) or high dose (25x106) Balb/c-Nude BM cells (fully depleted of T cells by virtue of the 'nude' phenotype) were transplanted (day 0) into fully allogeneic recipients (C3H/Hen). Conditioning included T cell debulking (TCD) with anti-CD4 and anti-CD8 antibodies (300µg each) delivered on day -6, and exposure to 2.0 Gy total body irradiation (TBI) on day -1. High dose Cyclophosphamide (CY) (100mg/kg) was administered on days +3 and +4. Chimerism analysis on days 35, 95, 180 and 225 revealed that none of the BM recipients that were transplanted with a regular dose of 5x106 T depleted BM in the presence or absence of CY, expressed donor type chimerism. In contrast , 4/7 mice receiving 25x106 cells and CY, exhibited (on day 225) more than 47.7±9. % multi-lineage chimerism. The stability of chimerism over more than 7 months indicated that tolerance was likely achieved. Indeed, this was confirmed by subsequent acceptance of donor type Balb/c skin grafts. Thus, 3/4 chimeric mice accepted Balb/c skin and rejected 3rd party C57BL/6 skin, while all mice that were inoculated with regular dose of BM cells in conjunction with CY (7/7), rejected both donor and 3rd party grafts. Encouraged by these results, we attempted to determine the optimal CY and radiation dose, to improve chimerism induction. Thus, mice receiving increasing CY dose of 125 or 150 mg /kg did not exhibit significant enhancement of chimerism. In addition, as shown in Fig1, while most of the recipients that were irradiated with 2Gy (13/15), 2.5Gy (6/6), 3Gy (4/5), or 3.5Gy, TBI (5/5) did not differ significantly in chimerism level (average= 69.1±24.7% at 300 days post transplant), further reduction of irradiation dose to 1.0Gy TBI, resulted in significantly reduced chimerism (average=25.4±26.2%, p≤0.003 ). Importantly, acceptance of donor type skin graft was further manifested when tested in chimeric mice conditioned with 2GY (9/13), while 3rd party skin was completely rejected (Fig.1). Considering previous suggestions by Ildstad et al. that a subset of CD8+ TCR- BM cells is critical for achieving donor type chimerism, we next determined whether such cells are indeed critical for engraftment of megadose T cell depleted BM transplants. To that end, CD8+ cells were depleted from the Balb/c -'nude' mega dose BM preparation, and chimerism induction was compared to control non-depleted 'nude' BM cells. The results of two independent experiments revealed no significant difference (P≥0.9974) in chimerism levels between mice transplanted in the presence (47.3±31, n=16) or absence (47.3±29, n=15) of CD8+TCR- cells, suggesting that such cells are not essential when using megadose T cell depleted transplants in conjunction with CY. Taken together, our results demonstrate that combination of T cell depleted megadose hematopoietic stem cells with CY administration post transplantation can lead to marked chimerism following low intensity conditioning, in contrast to using each approach alone. Importantly, there is no need to preserve CD8+TCR- cells in the transplant preparation. Such transplants, which are completely free of GVHD risk, could potentially pave the way for a safer tolerance induction modality in organ transplantation and in other non-malignant indications in which the risk associated with GVHD is not justified. Disclosures: Reisner: Cell Source LTD: Consultancy, Equity Ownership, Patents & Royalties, Research Funding.

166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2684-2691 ◽  
Author(s):  
Sergio Giralt ◽  
William Bensinger ◽  
Mark Goodman ◽  
Donald Podoloff ◽  
Janet Eary ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Phase 1 ◽  
High Dose ◽  
Two Phase ◽  
Hematopoietic Stem

Abstract Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation. (Blood. 2003;102:2684-2691)

scholarly journals Symptom Burden of Busulfan and Melphalan Versus Melphalan Alone for Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 681-681
Author(s):  
Loretta A. Williams ◽  
Muzaffar H. Qazilbash ◽  
Qiuling Shi ◽  
Qaiser Bashir ◽  
Huei K. Lin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Muscle Weakness ◽  
Symptom Severity ◽  
Conditioning Regimen ◽  
Symptom Burden ◽  
Phase Iii ◽  
Dry Mouth ◽  
Fixed Dose ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Background: High-dose melphalan 200 mg/m2 (Mel) is the standard for autologous hematopoietic stem cell transplantation (autoHSCT) for multiple myeloma. Retrospective analyses suggested that a combination of busulfan and melphalan (Bu-Mel) may be associated with a longer progression-free survival (PFS). A secondary aim of a randomized, phase III trial that compared the safety and efficacy of Bu-Mel vs Mel was to compare the symptom burden of the two regimens. Symptom burden is the combined impact of disease- and therapy-related symptoms on patient functional ability. Methods: Patients were randomized to Bu-Mel (Bu 130 mg/m2 daily for 4 days, either as a fixed dose or to target an average daily area under the curve of 5000 μmol-min, followed by 2 daily doses of Mel 70 mg/m)2or Mel (Mel 100 mg/m2 daily for 2 days). A subset of patients completed the 20 symptom severity and 6 interference items of MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM) prior to the start of the treatment regimen and weekly for 4 weeks post autoHSCT. Symptoms and interference are rated on 0-10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Differences in individual symptom severity and interference between the two arms were assessed by t-tests and mixed modeling. Results: As previously reported, 204 (Bu-Mel: 104, Mel: 100) were enrolled between October 2011 and March 2017. At last evaluation, 52 (51%) and 49 (49%) patients achieved a CR (p=0.88), and 69 (68%) and 67 (67%) patients achieved a CR+nCR (p=0.88) in Bu-Mel and Mel arms, respectively. Median PFS was 64.7 months and 34.4 months (p=0.013) in Bu-Mel and Mel arms, respectively. There was no difference in OS between the two arms. One hundred sixty-five of the patients (Bu-Mel: 81, Mel: 84) completed at least one MDASI-MM assessment. Median ages at autoHSCT were 57.2 and 57.0 years in Bu-Mel and Mel groups, respectively (p=0.86). At baseline, t-tests showed significantly higher mean severity of constipation (1.80, standard deviation [SD] = 2.87 vs 0.98, SD = 1.94; p=0.036), muscle weakness (2.38, SD=2.49 vs 1.44, SD=1.87; p=0.034), diarrhea (1.45, SD=2.43 vs 0.60, SD=1.10; p=0.005), and global symptom interference (2.96, SD=2.81 vs 1.77, SD=2.00; p=0.003) in the Bu-Mel arm than the Mel arm. The Bu-Mel patients had a significantly higher mean severity of pain (5.67, SD=2.65 vs 3.17, SD=3.07; p=0.0043) and mouth sores (7.35, SD=2.41 vs 1.25, SD=2.22; p <0.0001) than the Mel patients 7 days post autoHSCT. Longitudinal analysis using mixed modeling showed that the Bu-Mel arm had a significantly higher mean severity of pain (ED = 1.102, p=0.003), drowsiness (ED = 0.674, p=0.040), dry mouth (ED = 0.904, p=0.009), constipation (ED = 0.695, p=0.006), muscle weakness (ED = 0.815, p=0.006), mouth sores (ED = 1.683, p <0.0001), rash (ED = 0.362, p=0.019), and interference with physical functions (general activity: ED = 1.015, p=0.010; working: ED=1.229, p=0.006; walking: ED=0.920, p=0.009) than the Mel arm during the 4 weeks following autoHSCT. Conclusions: Patients receiving Bu-Mel vs Mel prior to autoHSCT report some differences in symptom severity, with Bu-Mel patients experiencing more severe sore mouth, pain, and symptom interference with daily functioning. The greater intensity of the double-alkylating agent conditioning regimen of Bu-Mel likely led to these differences. The increased severity of drowsiness, dry mouth, constipation, and muscle weakness may be due to an increased need for opioids to control severe pain and mouth sores. The effect of significant differences in symptom severity and interference at baseline between these two groups, despite randomization, is not clear. However, the longer time to progression of myeloma with the Bu-Mel regimen may offset the greater symptom burden early post autoHSCT. Systematic measurement of symptom burden during clinical trials can provide useful information for clinicians and patients in evaluating the full impact of different treatment regimens and enhance treatment decision making and discussion between clinicians and patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals A complex of methods of radiation diagnostics in a patient with multiple myeloma (clinical case)

2020 ◽  
Vol 24 (4) ◽  
pp. 133-145
Author(s):  
E. V. Kryukov ◽  
V. N. Troyan ◽  
O. A. Rukavitsyn ◽  
S. A. Alekseev ◽  
S. I. Kurbanov ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Multiple Myeloma ◽  
Autologous Transplantation ◽  
Emission Tomography ◽  
High Dose ◽  
High Dose Therapy ◽  
Hematopoietic Stem ◽  
X Ray ◽  
Positron Emission ◽  
Pet Ct

The article presents the possibilities of the complex application of methods of radiation diagnostics: bone x-ray, dual-energy X-ray absorptiometry, computed tomography, positron emission tomography combined with computed tomography using fluorodeoxyglucose labeled with 18-fluorine (PET/CT with 18F-FDG) in a patient with multiple myeloma, which was treated in the amount of high-dose therapy with autologous transplantation of hematopoietic stem cells. The diagnosis was established immunohistochemically. The use of these methods allowed us to dynamically assess the pathological changes characteristic of multiple myeloma.

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