Approximately 12% of all cancers worldwide are associated with viral infections. To date, eight viruses have been shown to contribute to the development of human cancers, including Epstein-Barr virus ...（EBV）, Hepatitis B and C viruses, and Human papilloma virus, among others. These DNA and RNA viruses produce oncogenic effects through distinct mechanisms. First, viruses may induce sustained disorders of host cell growth and survival through the genes they express, or may induce DNA damage response in host cells, which in turn increases host genome instability. Second, they may induce chronic inflammation and secondary tissue damage favoring the development of oncogenic processes in host cells. Viruses like HIV can create a more permissive environment for cancer development through immune inhibition, but we will focus on the previous two mechanisms in this review. Unlike traditional cancer thera- pies that cannot distinguish infected cells from non-infected cells, immunotherapies are uniquely equipped to target virus-associated malignancies. The targeting and functioning mechanisms associated with the immune response can be exploited to prevent viral infections by vaccination, and can also be used to treat infection before cancer establish- ment. Successes in using the immune system to eradicate established malignancy by selective recognition of virus-as- sociated tumor cells are currently being reported. For example, numerous clinical trials of adoptive transfer of ex vivo generated virus-specific T ceils have shown benefit even for established tumors in patients with EBV-associated malignancies. Additional studies in other virus-associated tumors have also been initiated and in this review we de- scribe the current status of immunotherapy for virus-associated malignancies and discuss future prospects.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The multiple mechanisms used by solid tumors to suppress tumor-specific immune responses are a major barrier to the success of adoptively transferred tumor-specific T cells. As viruses induce potent ...innate and adaptive immune responses, we hypothesized that the immunogenicity of viruses could be harnessed for the treatment of solid tumors if virus-specific T cells (VST) were modified with tumor-specific chimeric antigen receptors (CAR). We tested this hypothesis using VZV-specific T cells (VZVST) expressing a CAR for GD2, a disialoganglioside expressed on neuroblastoma and certain other tumors, so that the live-attenuated VZV vaccine could be used for
stimulation.
We generated GMP-compliant, GD2.CAR-modified VZVSTs from healthy donors and cancer patients by stimulation of peripheral blood mononuclear cells with overlapping peptide libraries spanning selected VZV antigens, then tested their ability to recognize and kill GD2- and VZV antigen-expressing target cells.
Our choice of VZV antigens was validated by the observation that T cells specific for these antigens expanded
after VZV vaccination. VZVSTs secreted cytokines in response to VZV antigens, killed VZV-infected target cells and limited infectious virus spread in autologous fibroblasts. However, while GD2.CAR-modified VZVSTs killed neuroblastoma cell lines on their first encounter, they failed to control tumor cells in subsequent cocultures. Despite this CAR-specific dysfunction, CAR-VZVSTs retained functional specificity for VZV antigens via their TCRs and GD2.CAR function was partially rescued by stimulation through the TCR or exposure to dendritic cell supernatants.
Vaccination via the TCR may provide a means to reactivate CAR-T cells rendered dysfunctional by the tumor microenvironment (NCT01953900).
.
We evaluated the impact of
FLT3
-ITD,
NPM1
mutations, and double mutant
CEBPa
(
dmCEBPa
) on overall survival (OS) after relapse in patients with cytogenetically intermediate-risk acute myeloid ...leukemia (AML) who were treated with chemotherapy alone in the first remission (CR1). Patients aged 16–65 years diagnosed with cytogenetically intermediate-risk AML, and who achieved CR1 were included. We retrospectively analyzed
FLT3
-ITD,
NPM1
mutations and
CEBPa
using samples obtained at diagnosis, which therefore did not affect the therapeutic decisions. Among 235 patients who had achieved CR1, 152 relapsed, and 52% of them achieved second CR. The rate of achieving second CR was significantly higher (85%) in those with
dmCEBPa
. Patients with
FLT3
-ITD had significantly worse OS after relapse than those without (19% vs 41%,
p
= 0.002), while OS was comparable between patients with and without
NPM1
mutations (37% vs 34%,
p
= 0.309). Patients with dm
CEBPa
had improved OS than those without (61% vs 32%,
p
= 0.006). By multivariate analysis,
FLT3
-ITD was independently associated with worse OS after relapse hazard ratio (HR) 1.99, 95% CI 1.27–3.12,
p
= 0.003, and
dmCEBPa
with improved OS (HR 0.40, 95% CI 0.17–0.93,
p
= 0.033). Our data show that screening for these mutations at diagnosis is useful for facilitating effective therapeutic decision-making even after relapse.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A series of abdominal computed tomography scans of an asymptomatic 40-year-old woman with a history of umbilical cord blood transplantation (CBT) for leukemia at 19 years old revealed the long-term ...gradual development of a right hepatic vein thrombus and stenosis of the inferior vena cava, leading to a diagnosis of Budd-Chiari syndrome. The Budd-Chiari syndrome in this case might have been influenced by the patient's history of multiple liver abscesses after CBT and associated thrombus formation, in addition to the hormone replacement therapy with estradiol and dydrogesterone she was taking. This case provides insight into the development of Budd-Chiari syndrome.
The outcome of therapy with chimeric Ag receptor (CAR)-modified T cells is strongly influenced by the subset origin of the infused T cells. However, because polyclonally activated T cells acquire a ...largely CD45RO
CCR7
effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T cell product. To determine the contribution of naive T cell, memory stem T cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cell populations to the CD3 and CD28-activated CAR-modified T cells that we use for therapy, we followed the fate and function of individually sorted CAR-modified T cell subsets after activation with CD3 and CD28 Abs (CD3/28), transduction and culture alone, or after reconstitution into the relevant subset-depleted population. We show that all subsets are sensitive to CAR transduction, and each developed a distinct T cell functional profile during culture. Naive-derived T cells showed the greatest rate of proliferation but had more limited effector functions and reduced killing compared with memory-derived populations. When cultured in the presence of memory T cells, naive-derived T cells show increased differentiation, reduced effector cytokine production, and a reduced reproliferative response to CAR stimulation. CD3/28-activated T cells expanded in IL-7 and IL-15 produced greater expansion of memory stem T cells and central memory T cell-derived T cells compared with IL-2. Our strategy provides a powerful tool to elucidate the characteristics of CAR-modified T cells, regardless of the protocol used for expansion, reveals the functional properties of each expanded T cell subset, and paves the way for a more detailed evaluation of the effects of manufacturing changes on the subset contribution to in vitro-expanded T cells.
ABSTRACT
Allogeneic hematopoietic stem cell transplantation (allo‐HSCT), a curative treatment for hematopoietic neoplasms, often causes various autoimmune disease‐like conditions. In contrast, ...allo‐HSCT‐related type 1 diabetes mellitus is extremely rare. Herein, we report a case of allo‐HSCT‐related type 1 diabetes mellitus in a patient who had undergone cord blood transplantation (CBT) as a treatment for acute myeloid leukemia. The patient's human leukocyte antigen was replaced with the donor type after transplantation. The donor had a disease‐sensitive haplotype. To the best of our knowledge, this is the first reported case of type 1 diabetes mellitus following CBT.
After CBT, we noted elevated FBS levels and positivity for anti‐GAD antibodies (25.6 U/mL). The patient developed an insulin‐dependent state as the C‐peptide immunoreactivity index decreased with time.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Introduction
Primary prostate lymphomas are very rare; however, the incidence of malignant lymphoma is high among HIV‐infected patients. Herein, we report a case of primary diffuse large B‐cell ...lymphoma (DLBCL) of the prostate in an HIV‐infected patient.
Case presentation
A 47‐year‐old man presented with miction pain and back pain. Abdominal CT revealed a huge prostate mass extending to the left retroperitoneum. Serum sIL‐2R level was abnormally high (2896 U/mL), whereas PSA level was normal. HIV antigen and antibody tests were positive. The patient was diagnosed with DLBCL after a prostate biopsy. Systemic treatments were administered; however, the tumor was refractory, and the patient died 9 months after diagnosis.
Conclusion
Prostate malignant lymphomas are rare but should be considered in patients with enlarged prostates and normal PSA levels. It should be noted that HIV patients have a high incidence of malignant lymphomas.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Although rather favorable probabilities of return to work have been reported after allogeneic hematopoietic cell transplantation (allo-HCT), survivors often have difficulty continuing to ...work because of their immunocompromised status and diverse late effects after allo-HCT. We evaluated the incidence of and risk factors for recurrent sick leave in allo-HCT survivors after they initially returned to work.
Methods
We targeted allo-HCT survivors who were employed at diagnosis, aged 20–64 at survey, and survived for ≥ 2 years without relapse. Of the 1904 survivors who were informed of the study, 1148 returned the questionnaire (60%), and 1048 eligible participants were included in the overall analysis. In the present study that considered recurrent sick leave after return to work, we targeted 896 participants who returned to work at least once after allo-HCT. Participants stated if they had recurrent sick leave after returning to work and its reasons, as well as associated patient-, HCT/HCT center–, and work-related factors and clinical events after allo-HCT. A logistic regression analysis was conducted to explore correlated factors for recurrent sick leave.
Results
In survivors who returned to work, 30% required recurrent sick leave. The most frequent causes of recurrent leave were physical issues (72%), and analysis of free descriptions demonstrated that these were mainly associated with graft-versus-host disease, infection, or readmission. Other reasons included work-related issues such as gap between physical and working conditions. Multivariate analysis showed that cord blood transplantation, longer employment duration, and counseling from healthcare professionals were associated with a lower risk of recurrent leave. Readmission, immunosuppressant use, and symptoms involving the respiratory system, gut, and joints and muscles were associated with a higher risk.
Conclusions
Our results drawn from a large cohort study should help healthcare professionals identify and assist at-risk patients. Multi-professional teams that provide continuous support and effective communication with the workplace are necessary to improve long-term outcomes after allo-HCT.
Implications for Cancer Survivors
In order to continue working after the initial return to work, it is important to receive counseling from healthcare professionals and obtain reasonable accommodation from workplace.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
BackgroundC-type lectin-like molecule 1 (CLL-1) is highly expressed in acute myeloid leukemia (AML) but is absent in primitive hematopoietic progenitors, making it an attractive target for a chimeric ...antigen receptor (CAR) T-cell therapy. Here, we optimized our CLL-1 CAR for anti-leukemic activity in mouse xenograft models of aggressive AML.MethodsFirst, we optimized the CLL-1 CAR using different spacer, transmembrane and costimulatory sequences. We used a second retroviral vector to coexpress transgenic IL15. We measured the effects of each construct on T cell phenotype and sequential (recursive) co culture assays with tumor cell targets to determine the durability of the anti tumor activity by flow cytometry. We administered CAR T cells to mice engrafted with patient derived xenografts (PDX) and AML cell line and determined anti tumor activity by bioluminescence imaging and weekly bleeding, measured serum cytokines by multiplex analysis. After euthanasia, we examined formalin-fixed/paraffin embedded sections. Unpaired two-tailed Student’s t-tests were used and values of p<0.05 were considered significant. Survival was calculated using Mantel-Cox log-rank test.ResultsIn vitro, CLL-1 CAR T cells with interleukin-15 (IL15) were less terminally differentiated (p<0.0001) and had superior expansion compared with CD28z-CD8 CAR T cells without IL15 (p<0.001). In both AML PDX and AML cell line animal models, CLL-1 CAR T coexpressing transgenic IL15 initially expanded better than CD28z-CD8 CAR T without IL15 (p<0.0001), but produced severe acute toxicity associated with high level production of human tumor necrosis factor α (TNFα), IL15 and IL2. Histopathology showed marked inflammatory changes with tissue damage in lung and liver. This acute toxicity could be managed by two strategies, individually or in combination. The excessive TNF alpha secretion could be blocked with anti-TNF alpha antibody, while excessive T cell expansion could be arrested by activation of an inducible caspase nine safety switch by administration of dimerizing drug. Both strategies successfully prolonged tumor-free survival.ConclusionCombinatorial treatment with a TNFα blocking antibody and subsequent activation of the caspase-9 control switch increased the expansion, survival and antileukemic potency of CLL-1 CAR T-cells expressing transgenic IL15 while avoiding the toxicities associated with excessive cytokine production and long-term accumulation of activated T-cells.
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