Graft-Versus-Host Disease

MSC Infusions Promising for GVHD After Haploidentical Transplant

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Still, many problems remain to be solved to optimize the procedure.

Infusions of mesenchymal stromal cells (MSCs) helped prevent chronic graft-versus-host disease (GVHD) in patients with blood malignancies who underwent HLA-haploidentical hematopoietic stem-cell transplantation (HSCT), according to the results of a randomized, controlled trial.

The 2-year cumulative incidence of chronic GVHD in the treatment group was 27.4% (95% CI 16.2%-38.6%) compared with 49% in the control group (95% CI 36.5%-61.5%), Xi Zhang, MD, PhD, of Xinqiao Hospital in Chongqing China, and colleagues reported in the Journal of Clinical Oncology.

 “We demonstrate for the first time, to our knowledge, that reduplicative infusion of MSCs after HLA-haplo HSCT can reduce the incidence of chronic GVHD, accompanied by changes in the number of Treg cells, memory B lymphocytes, and natural killer cells, as well as the Th1:Th2 cell ratio. Future studies to adjust the MSC infusion program and understand the underlying mechanism will enable us to elucidate the in vivo effects of MSCs and help facilitate their broad application.”

In an accompanying editorial, Hillard Lazarus, MD, of Case Western Reserve University in Cleveland, Ohio, and Steven Pavletic, MD, of the Experimental Transplantation and Immunology Branch, Graft-versus-Host and Autoimmunity Section, of the National Institutes of Health in Bethesda, Md., said that on the basis of the study, future investigations of chronic GVHD prophylaxis using MSCs should be explored.

“The permutations and combinations for using different cell sources for deriving the MSCs, and in the context of different neoplastic disease, type and stage, conditioning regimen intensity, GVHD prophylaxis, graft and donor source, among other variables, are daunting,” they said. “Nonetheless, the results of the [Zhang et al] trial encourage us to further explore this approach.”

The phase II, randomized, double-blind, controlled trial included 124 patients with hematologic malignancies who underwent HLA-haploidentical hematopoietic stem-cell transplantation at five transplantation centers. Eligible patients met the following criteria: acute GVHD did not occur or was controlled for more than 100 days after transplantation; lack of chronic GVHD at 100 days after transplantation; and the absence of uncontrolled infections and severe liver, renal, lung, and heart diseases.

Patients were randomized 1:1 to receive either monthly infusions of umbilical cord-derived MSCs or saline. The infusions began 4 months after the transplant and continued for up to 4 months. Patients were enrolled from 2009 to 2013 and were followed until 2015.

 The primary endpoint was the development of chronic GVHD. Secondary endpoints included overall survival, disease-free survival, relapse, and changes in immune system cells.

Chronic GVD developed in 17 patients in the treatment group versus 30 in the control group. Seven patients in the control group developed severe lung GVHD, versus none in the treatment group.

The number of natural killer cells tended to be lower in the treatment group, but there were no significant changes in the proportions of T or B lymphocytes in the treatment versus the control group. However, an analysis of T lymphocyte subsets found that the numbers of CD4+, CD25+, and CD127- regulatory T-cells were significantly higher in the treatment group.

The investigators also found that the numbers of CD27+ B lymphocytes were significantly increased in the treatment group after the MSC infusions compared with pretreatment values.

Zhang and colleagues also reported that the ratio of type 1 to type 2 T-helper cells increased almost two-fold after four MSC infusions, from 1.37 to 2.86. “This result indicates that the Th0 cells developed a differentiation imbalance and tended to become Th2 cells before the treatment with MSCs. After four MSC infusions, the proportion of Th1 cells gradually increased, and the proportion of Th2 cells gradually decreased,” the investigators said.

 “Specifically, these results indicate that infusion with MSCs plays a role in downregulating excessive Th0-to-Th2 differentiation and increasing the proportion of Th1 cells, thereby reversing the Th1:Th2 cell imbalance in patients after HSCT. However, the increasing trend in the Th1:Th2 cell ratio disappeared after day 28.”

Two-year overall survival rates were not significantly different in the treatment versus the control group (66% versus 61%), and neither were the 2-year disease-free survival rates (65% versus 60%).

The rates of relapse were not significantly different between the treatment and control groups (31% versus 32%).

The infusions were well tolerated, with no acute infusional toxicity and no adverse events associated with them, Zhang and colleagues said.

Limitations of the study included that the investigators did not provide specific details of the MSC preparative steps, did not indicate if all centers received cells from the same batch of MSCs, and did not provide the protocol for cell infusion, Lazarus and Pavletic said in their editorial.

“In addition, the authors do not discuss blinding of subjects or observers, which, obviously, is critical in any GVHD study.”

Vaccine stirs immune activity against advanced, hard-to-treat leukemia.

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Novel treatment boosted selective immune attack on leukemia cells in post-transplant patients

Patients with advanced chronic lymphocytic leukemia (CLL) often receive donor transplants that effectively “reboot” their own immune defenses, which then attack and potentially cure the hard-to-treat disease. However, there is a high rate of relapse in these patients, and the transplanted immune cells may also harm normal tissues, causing graft-versus-host disease (GVHD).

Now, scientists at Dana-Farber Cancer Institute report in the Journal of Clinical Investigation that they observed a strong and selective immune response in some patients who received, shortly after the transplant, several doses of a “personalized” tumor vaccine composed of their own inactivated leukemia cells combined with an immune stimulant, GM-CSF. Thus the vaccine boosted the power of the transplanted immune system’s ability to attack the cancer – known as the graft-versus-leukemia (GvL) effect.

“Our studies suggest that autologous tumor cell vaccination is an effective strategy to advance long-term leukemia control” following transplants from donors, saidCatherine Wu, MD, senior author. “Although this was a phase 1 study and not powered to look at questions of clinical efficacy, we did see promising clinical activity.”

There are few treatment options for advanced CLL. Standard transplants, which involve powerful doses of pre-transplant chemotherapy to wipe out as much of the leukemia as possible, have proven too toxic for older patients and those with co-existing diseases. Over the past decade, researchers have developed reduced-intensity conditioning (RIC) regimens, using lower chemotherapy doses that are more tolerable but which rely entirely on the activity of the transplanted immune cells to battle the leukemia. Usually this is insufficient to keep the cancer at bay long-term and the disease progresses.

Furthermore, research has shown that the identifying antigens on the surface of CLL cells in individual patients may differ – that is, they have “personal tumor antigens,” the scientists said. “Based on these principles, vaccination with autologous [the patient’s own stored leukemia cells] irradiated leukemia cells is an attractive approach to expand leukemia-reactive T cells, since this vaccine formulation reliably includes personal tumor antigens.”

To make the vaccine, the researchers mixed the patients’ irradiated leukemia cells with cells that produce GM-CSF (granulocyte-macrophage colony-stimulating factor) and then injected them back into the patient. The combination stirs up a strong response by immune T cells, and the distinctive antigens on the injected leukemia cells direct the T cells to attack similar leukemia cells wherever they are present in the body.

In the phase 1 trial, the vaccine was administered between 30 and 100 days after the transplant, with some patients receiving as many as six vaccine doses. The study enrolled 22 patients with advanced, aggressive CLL. Thirteen of the patients had evidence of the leukemia in their bone marrow at the time of transplant.

Four patients did not receive the vaccine because they developed GVHD following the transplant. The remaining 18 received at least one vaccine dose; seven patients stopped receiving the vaccine after they developed GVHD.

When examined six months post-transplant, the majority of patients showed evidence of clinical response: 10 had complete remissions and six had partial remissions. After a median follow-up of 2.9 years, 13 patients (72 percent) had remained in continuous complete remission; one patient had stable disease, three patients developed progressive disease and two of those patients died.

The results support the safety and biological activity of whole tumor-cell vaccination in hematological malignancies, said the authors, and that giving the vaccine shortly after transplant may have been critical in its effectiveness. In addition, they said a key to the vaccine’s potency was the development by Dana-Farber scientists of GM-CSF-secreting “bystander” cells that can be used against lymphoid malignancies – which was not possible previously.

However, the authors noted that further randomized studies in larger patient groups will be necessary to determine if this strategy “will translate into a true clinical benefit for patients with advanced CLL.”

Source:DFCI

Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome.

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BACKGROUND

Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin.

METHODS

We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls.

RESULTS

DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease.

CONCLUSIONS

We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen.

Souirce: NEJM

 

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Sequence-Based Discovery of Bradyrhizobium enterica in Cord Colitis Syndrome
BACKGROUND
Immunosuppression is associated with a variety of idiopathic clinical syndromes that may have infectious causes. It has been hypothesized that the cord colitis syndrome, a complication of umbilical-cord hematopoietic stem-cell transplantation, is infectious in origin.
METHODS
We performed shotgun DNA sequencing on four archived, paraffin-embedded endoscopic colon-biopsy specimens obtained from two patients with cord colitis. Computational subtraction of human and known microbial sequences and assembly of residual sequences into a bacterial draft genome were performed. We used polymerase-chain-reaction (PCR) assays and fluorescence in situ hybridization to determine whether the corresponding bacterium was present in additional patients and controls.
RESULTS
DNA sequencing of the biopsy specimens revealed more than 2.5 million sequencing reads that did not match known organisms. These sequences were computationally assembled into a 7.65-Mb draft genome showing a high degree of homology with genomes of bacteria in the bradyrhizobium genus. The corresponding newly discovered bacterium was provisionally named Bradyrhizobium enterica. PCR identified B. enterica nucleotide sequences in biopsy specimens from all three additional patients with cord colitis whose samples were tested, whereas B. enterica sequences were absent in samples obtained from healthy controls and patients with colon cancer or graft-versus-host disease.
CONCLUSIONS
We assembled a novel bacterial draft genome from the direct sequencing of tissue specimens from patients with cord colitis. Association of these sequences with cord colitis suggests that B. enterica may be an opportunistic human pathogen.
Source: NEJM

 

ST2 as a Marker for Risk of Therapy-Resistant Graft-versus-Host Disease and Death

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BACKGROUND

No plasma biomarkers are associated with the response of acute graft-versus-host disease (GVHD) to therapy after allogeneic hematopoietic stem-cell transplantation.

METHODS

We compared 12 biomarkers in plasma obtained a median of 16 days after therapy initiation from 10 patients with a complete response by day 28 after therapy initiation and in plasma obtained from 10 patients with progressive GVHD during therapy. The lead biomarker, suppression of tumorigenicity 2 (ST2), was measured at the beginning of treatment for GVHD in plasma from 381 patients and during the first month after transplantation in three independent sets totaling 673 patients to determine the association of this biomarker with treatment-resistant GVHD and 6-month mortality after treatment or transplantation.

RESULTS

Of the 12 markers, ST2 had the most significant association with resistance to GVHD therapy and subsequent death without relapse. As compared with patients with low ST2 values at therapy initiation, patients with high ST2 values were 2.3 times as likely to have treatment-resistant GVHD (95% confidence interval [CI], 1.5 to 3.6) and 3.7 times as likely to die within 6 months after therapy (95% CI, 2.3 to 5.9). Patients with low ST2 values had lower mortality without relapse than patients with high ST2 values, regardless of the GVHD grade (11% vs. 31% among patients with grade I or II GVHD and 14% vs. 67% among patients with grade III or IV GVHD, P<0.001 for both comparisons). Plasma ST2 values at day 14 after transplantation were associated with 6-month mortality without relapse, regardless of the intensity of the conditioning regimen.

CONCLUSIONS

ST2 levels measured at the initiation of therapy for GVHD and during the first month after transplantation improved risk stratification for treatment-resistant GVHD and death without relapse after transplantation.

Source: NEJM

 

Biomarkers Predict Outcome of Graft-Versus-Host Disease.

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A six-protein biomarker panel predicted mortality and response to GVHD therapy.

A limiting factor in allogeneic hematopoietic cell transplantation is the development of graft-versus-host disease (GVHD). Having the ability to predict response to GVHD-treatment and survival might improve transplant outcomes.

To achieve this goal, investigators collected serum from 112 patients with newly diagnosed acute GVHD and evaluated six biomarkers: tumor necrosis factor receptor-1, interleukin-2-receptor-α, interleukin-8, hepatocyte growth factor, regenerating islet-derived 3-α, and elafin (a skin-specific marker). The relative effects of each biomarker were summarized, and a threshold was set for defining high versus low biomarker panel values.

Results were as follows:

  • Individuals with high biomarker panel values (32 patients) versus low values (80 patients) at inception experienced worse 180-day mortality (56% vs. 21%; odds ratio, 4.76; P<0.0001).
  • High panel values at inception independently predicted 180-day mortality after adjustment for onset of GVHD grade (II/IV vs. I/II), relatedness of donor, and stem cell source (OR, 4.61; P<0.001).
  • High panel values at inception predicted nonresponse to GVHD therapy at day 28 after adjustment for onset of GVHD grade (OR, 2.98; P=0.017).
  • Patients with high panel values at day 14 were more likely to be nonresponsive to treatment at day 28 (56% vs. 17%; OR, 6.32; P<0.001).
  • Patients with high panel values at day 28 experienced worse 180-day mortality (49% vs. 87%; OR, 7.22; P<0.0001).
  • Including panel values at day 28 with other predictors of 180-day mortality provided an additional independent predictor (OR, 7.43; P<0.001).

Comment: Acute GVHD is a major factor affecting the survival of patients following allogeneic transplantation. Because steroids and other agents affect the course of the disease in various ways, predicting outcome in individual patients has been difficult. If the biomarker panel described by these authors is validated in a more heterogeneous clinical sample, it will be helpful in managing this challenging disorder.

Source: Journal Watch Oncology and Hematology