Adoptive cell therapy has emerged as a powerful treatment for advanced cancers resistant to conventional agents. Most notable are the remarkable responses seen in patients receiving autologous ...CD19-redirected chimeric antigen receptor (CAR) T cells for the treatment of B lymphoid malignancies; however, the generation of autologous products for each patient is logistically cumbersome and has restricted widespread clinical use. A banked allogeneic product has the potential to overcome these limitations, yet allogeneic T-cells (even if human leukocyte antigen-matched) carry a major risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are bone marrow-derived innate lymphocytes that can eliminate tumors directly, with their activity governed by the integration of signals from activating and inhibitory receptors and from cytokines including IL-15, IL-12, and IL-18. NK cells do not cause GVHD or other alloimmune or autoimmune toxicities and thus, can provide a potential source of allogeneic "off-the-shelf" cellular therapy, mediating major anti-tumor effects without inducing potentially lethal alloreactivity such as GVHD. Given the multiple unique advantages of NK cells, researchers are now exploring the use of CAR-engineered NK cells for the treatment of various hematological and non-hematological malignancies. Herein, we review preclinical data on the development of CAR-NK cells, advantages, disadvantages, and current obstacles to their clinical use.
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of ...the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia CLL). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×10
, 1×10
, or 1×10
CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.).
The landscape of HLA matching in hematopoietic cell transplantation (HCT) is continuously advancing, introducing more nuanced criteria beyond traditional 10/10 HLA-A, -B, -C, and -DRB1 allele ...matching. For 10/10 matched donors, prioritizing a donor with a “core” permissive HLA-DPB1 mismatch is recommended over “noncore” permissive mismatches, with nonpermissive mismatches being the least prefered. In the one-antigen mismatched setting (7/8 HLA-matched), HLA-C matching, particularly avoiding high-expression mismatches at residues 116 or 77/80, is preferred over HLA-A or HLA-B mismatches. HLA B-leader matching is beneficial in both one-antigen mismatched and haploidentical HCT. Additionally, specific HLA mismatches in haploidentical HCT, such as DRB1 mismatches with DQB1 matches and DPB1 nonpermissive mismatches are linked to better outcomes. Among non-HLA factors, evidence consistently underscores the pivotal impact of donor age on overall survival. For HLA-mismatched transplants, including haploidentical HCT, avoidance of donors against whom the recipient has preformed donor-specific antibodies is paramount. Selecting a cytomegalovirus (CMV) seronegative donor is important particularly for CMV-negative recipients; however, more research is needed in the letermovir prophylaxis era. The impact of ABO-matching on transplant outcomes is debatable. Other unanswered questions include defining “younger” donors and establishing hierarchy in donor selection based on factors like CMV status, ABO compatibility, or sex-mismatch, to name a few. Future research addressing these issues will refine donor selection algorithms and improve transplant success. In conclusion, selecting a donor for HCT requires multifaceted considerations, integrating evolving HLA-matching criteria and non-HLA factors, to optimize HCT outcomes in this rapidly advancing field.
Infection is the leading cause of non-relapse mortality after allogeneic haematopoietic cell transplantation (HCT). This occurs as a result of dysfunction to the host immune system from the ...preparative regimen used prior to HCT, combined with a delay in reconstitution of the donor-derived immune system after HCT. In this article, we elaborate on the process of immune reconstitution post-HCT that begins with the innate system and is followed by recovery of adaptive immunity. Simultaneously, we describe how the tempo of immune reconstitution influences the risk of various infections. We explain some of the key differences in immune reconstitution and the consequent risk of infections in recipients of peripheral blood stem cell, bone marrow or umbilical cord blood grafts. Other factors that impact on immune recovery are also highlighted. Finally, we allude to various strategies that are being tested to enhance immune reconstitution post-HCT.
NK cell therapy for hematologic malignancies Mehta, Rohtesh S.; Randolph, Brion; Daher, May ...
International journal of hematology,
03/2018, Letnik:
107, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Natural killer (NK) cells are part of the innate immune system and represent the first line of defense against infections and tumors. In contrast to T cells, NK cells do not require prior antigen ...sensitization to induce cytotoxicity and do not cause graft-versus-host disease. These, along with other advantages, make NK cells an attractive candidate for adoptive cellular therapy. Herein, we describe the mechanisms of NK cell cytotoxicity, which is governed by an intricate balance between various activating and inhibitory receptors, including the killer cell immunoglobulin-like receptors (KIRs). We illustrate the advantages of NK alloreactivity as demonstrated in various types of hematopoietic stem cell transplants (HSCT), such as haploidentical, human leukocyte antigen-matched related or unrelated donor and umbilical cord blood transplant. We elaborate on different models used to predict NK cell alloreactivity in these studies, which are either based on the absence of the ligands for inhibitory KIRs, presence of activating NK cell receptors and KIR genes content in donors, or a combination of these. We will review clinical studies demonstrating anti-tumor efficacy of NK cells used either as a stand-alone immunotherapy or as an adjunct to HSCT and novel genetic engineering strategies to improve the anti-tumor activity of NK cells.
Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 ...and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval CI, 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481.
Posttransplant cyclophosphamide (PTCy) graft-versus-host disease (GVHD) prophylaxis has enabled haploidentical (Haplo) transplantation to be performed with results similar to those after matched ...unrelated donor (MUD) transplantation with traditional prophylaxis. The relative value of transplantation with MUD vs Haplo donors when both groups receive PTCy/calcineurin inhibitor/mycophenolate GVHD prophylaxis is not known. We compared outcomes after 2036 Haplo and 284 MUD transplantations with PTCy GVHD prophylaxis for acute leukemia or myelodysplastic syndrome in adults from 2011 through 2018. Cox regression models were built to compare outcomes between donor types. Recipients of myeloablative and reduced-intensity regimens were analyzed separately. Among recipients of reduced-intensity regimens, 2-year graft failure (3% vs 11%), acute grades 2 to 4 GVHD (hazards ratio HR, 0.70; P = .022), acute grades 3 and 4 GVHD (HR, 0.41; P = .016), and nonrelapse mortality (HR, 0.43; P = .0008) were lower after MUD than with Haplo donor transplantation. Consequently, disease-free (HR, 0.74; P = .008; 55% vs 41%) and overall (HR, 0.65; P = .001; 67% vs 54%) survival were higher with MUD than with Haplo transplants. Among recipients of myeloablative regimens, day-100 platelet recovery (95% vs 88%) was higher and grades 3 and 4 acute (HR, 0.39; P = .07) and chronic GVHD (HR, 0.66; P = .05) were lower after MUD than with Haplo donor transplantation. There were no differences in graft failure, relapse, nonrelapse mortality, and disease-free and overall survival between donor types with myeloablative conditioning regimens. These data extend and confirm the importance of donor-recipient HLA matching for allogeneic transplantation. A MUD is the preferred donor, especially for transplantations with reduced-intensity conditioning regimens.
Introduction
Several factors, including race, age, stage, comorbid conditions, social support, and socioeconomic status, have been linked to the likelihood of a patient having surgery for early-stage ...non-small cell lung cancer (NSCLC). The aim of the present study is to determine the influence of race and health disparities on refusal of recommended potentially curative surgery.
Methods
The Surveillance, Epidemiology, and End Results (SEER) database was used to create a cohort of 62,514 patients diagnosed with stages I and II NSCLC between 1988 and 2002, of whom 51,938 were recommended for surgery. The outcome variable was refusal of recommended surgical treatment, while race was the key predictor variable. Potential confounders were adjusted for in the hierarchical generalized logistic regression analysis.
Results
A majority was White (86%) and underwent surgery (81%). About 2% of Blacks (
n
= 109), 1.4% of Whites (
n
= 756), and 2.8% of “other” race individuals (
n
= 96) refused surgery. In the multivariable adjusted model, Blacks odds ratio (OR) 1.95, 95% confidence interval (CI) 1.5, 2.3,
P
< 0.001 and those of “other” race (OR 2.03, 95% CI 1.5, 2.5,
P
< 0.001) had greater odds of refusing surgery than did Whites. Increasing age, male gender (OR 1.17,
P
= 0.031), and being unmarried (OR 2.1,
P
< 0.001) were other factors associated with higher odds of refusal. Significant county variations were also noted in refusal of surgery.
Conclusions
Blacks and “other” races are more likely to refuse recommended surgery for early-stage NSCLC compared with Whites. Future studies should focus on exploring potential reasons for refusal and developing communication interventions.
Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host disease (cGVHD) in the presence of increased HLA ...disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of interleukin-10 (IL-10)-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear. Here, we demonstrate that CB contains an abundance of B cells with immunoregulatory function. Bregs were identified in both the naive and transitional B-cell compartments and suppressed T-cell proliferation and effector function through IL-10 production as well as cell-to-cell contact involving CTLA-4. We further show that the suppressive capacity of CB-derived Bregs can be potentiated through CD40L signaling, suggesting that inflammatory environments may induce their function. Finally, there was robust recovery of IL-10–producing Bregs in patients after CB transplantation, to higher frequencies and absolute numbers than seen in the peripheral blood of healthy donors or in patients before transplant. The reconstituting Bregs showed strong in vitro suppressive activity against allogeneic CD4+ T cells, but were deficient in patients with cGVHD. Together, these findings identify a rich source of Bregs and suggest a protective role for CB-derived Bregs against cGVHD development in CB recipients. This advance could propel the development of Breg-based strategies to prevent or ameliorate this posttransplant complication.
•Cord blood is a rich source of B cells with immunoregulatory function.•IL-10–producing B cells may protect against cGVHD after cord blood transplantation.
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