Treatment of Multiple Myeloma With Daratumumab in a Kidney Transplant Patient.

CLINICAL FEATURES: A middle-aged man with history of kidney transplantation was diagnosed with multiple myeloma (MM); he was treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for induction therapy. However, a repeat bone marrow biopsy after treatment revealed 10% clonal plasma cell involvement. Given residual disease, his treatment regimen was changed to daratumumab, bortezomib, and dexamethasone in an attempt to achieve minimal residual disease. THERAPEUTIC CHALLENGE: Daratumumab was recently approved for treatment of relapsed or refractory MM; there are no data regarding the safety and effectiveness in solid organ transplant patients. SOLUTION: Our patient was treated with a daratumumab-based regimen for MM. His renal function was monitored closely along with donor-specific antibody to assess for risk of graft rejection. His renal function remained stable with minimal proteinuria and negative donor-specific antibody during the treatment course.

Phase 1 clinical trial evaluating abatacept in patients with steroid-refractory chronic graft-versus-host disease.

Steroid-refractory chronic graft-versus-host disease (SR-cGVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. Innovative immunotherapeutic strategies are urgently needed for the treatment of SR-cGVHD. We conducted a phase 1 clinical trial to evaluate the safety, efficacy, and immune effects of abatacept, a novel immunomodulatory drug that acts as an inhibitor of T-cell activation via costimulatory blockade, in the treatment of SR-cGVHD. The study followed a 3+3 design with 2 escalating abatacept doses: 3 mg/kg and 10 mg/kg, with an expansion cohort treated at 10 mg/kg. Abatacept was well-tolerated with no dose-limiting toxicities. Of the 16 evaluable patients, 44% achieved a clinical partial response per 2005 National Institutes of Health Consensus Criteria. Importantly, abatacept resulted in a 51.3% reduction in prednisone usage in clinical responders (mean baseline, 27 vs 14 mg; P = .01). Increased PD-1 expression on circulating CD4 (P = .009) and CD8 (P = .007) T cells was observed in clinical responders. In summary, abatacept was safe and led to a marked improvement in National Institutes of Health cGVHD scores and a significant reduction in prednisone use. In this cohort of heavily pretreated patients, the results suggest abatacept may be a promising therapeutic agent for SR-cGVHD, and a phase 2 trial has been initiated. This trial was registered at www.clinicaltrials.gov as #NCT01954979.

Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine.

Acute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell-mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukaemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD-1 (also termed PDCD1) expressing T cells and reducing AML-mediated expansion of myeloid-derived suppressor cells. Therapy with guadecitabine results in enhanced leukaemia-specific immunity, as manifested by increased CD4 and CD8 cells targeting syngeneic leukaemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukaemia-specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti-leukaemia immunity and survival. The combination of a novel personalized dendritic cell/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned.

Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1.

Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK-STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies.

Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance.

BACKGROUND: Cutis laxa is a rare dermatosis that is inherited or acquired and clinically features loose, wrinkled, and redundant skin with decreased elasticity. This heterogeneous connective tissue disorder may be localized or generalized, with or without internal manifestations. Generalized cutis laxa often has a cephalocaudal progression and is attributed to inflammatory cutaneous eruptions, medications, and infections. Cutis laxa is also associated with several other conditions including rheumatoid arthritis, systemic lupus erythematosus, and plasma-cell dyscrasias. Case Presentation. We report an unusual case of a 35-year-old male with progression of generalized acquired cutis laxa and vasculitis that occurred over a period of one year. No cutaneous inflammatory eruption preceded or accompanied his decreased skin elasticity, and a biopsy of the skin showed elastolysis. His cutaneous manifestation led to systemic evaluation and an eventual diagnosis of smoldering multiple myeloma accompanied by aortitis and anemia. His myeloma and vasculitis were successfully treated with cyclophosphamide, bortezomib, and dexamethasone and high-dose prednisone, respectively, with no improvement to his cutis laxa. CONCLUSIONS: The presence of monoclonal gammopathy is strongly associated with several dermatological entities such as acquired cutis laxa. We propose a new term for the dermatological manifestations caused by paraproteinemia: monoclonal gammopathy of dermatological significance, or MGODS, and stress the evaluation of an underlying gammopathy in the setting of certain dermatologic conditions, including scleromyxedema and amyloidosis. We present a case of a newly acquired cutis laxa secondary to plasma-cell dyscrasias that exemplifies MGODS, alongside a brief literature review, and underscore the clinical relevance of monoclonal gammopathies of dermatological significance.

Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial.

BACKGROUND: Increased aurora A kinase (AAK) expression occurs in acute myeloid leukaemia; AAK inhibition is a promising therapeutic target in this disease. We therefore aimed to assess the activity of alisertib combined with 7 + 3 induction chemotherapy in previously untreated patients with high-risk acute myeloid leukaemia. METHODS: We did a single-arm, phase 2 trial of patients recruited from the Dana-Farber/Harvard Cancer Center in the USA. Eligible patients had previously untreated acute myeloid leukaemia, an Eastern Cooperative Oncology Group performance status of 0-2, and were at high risk of disease as defined by the presence of an adverse-risk karyotype, the presence of secondary acute myeloid leukaemia arising from previous myelodysplastic syndrome or myeloproliferative neoplasm, the presence of therapy-related acute myeloid leukaemia, or being 65 years or older. Enrolled patients received 7 + 3 induction chemotherapy of continuous infusion of cytarabine (100 mg/m2 per day on days 1-7) and intravenous bolus of idarubicin (12 mg/m2 per day on days 1-3). Oral alisertib (30 mg) was given twice per day on days 8-15. Patients could receive up to four consolidation cycles with cytarabine and alisertib, and alisertib maintenance for 12 months. The primary endpoint was a composite including the proportion of patients achieving complete remission and those with a complete remission with incomplete neutrophil or platelet count recovery. Analyses were per-protocol. This study is registered with Clinicaltrials.gov, number NCT02560025, and has completed enrolment. FINDINGS: Between Dec 31, 2015, and Aug 1, 2017, we enrolled a total of 39 eligible patients. 19 (49%) of 39 patients had secondary acute myeloid leukaemia and three (8%) had therapy-related acute myeloid leukaemia. At mid-induction, 33 (85%) of 39 patients showed marrow aplasia, six (15%) received re-induction. The median follow-up was 13·7 months (IQR 12·7-14·4). Composite remission was 64% (two-stage 95% CI 48-79), with 20 (51%) of 39 patients achieving complete remission and five (13%) achieving complete remission with incomplete neutrophil or platelet count recovery. The most common grade 3 or 4 adverse events included febrile neutropenia (16 [41%] of 39), neutropenia (12 [31%]), thrombocytopenia (13 [33%]), anaemia (11 [28%]), anorexia (nine [23%]), and oral mucositis (four [10%]). No treatment-related deaths were observed. INTERPRETATION: These results suggest that alisertib combined with induction chemotherapy is active and safe in previously untreated patients with high-risk acute myeloid leukaemia. This study met criteria to move forward to a future randomised trial. FUNDING: Millennium Pharmaceuticals.

Anti-cancer vaccine therapy for hematologic malignancies: An evolving era.

The potential promise of therapeutic vaccination as effective therapy for hematologic malignancies is supported by the observation that allogeneic hematopoietic cell transplantation is curative for a subset of patients due to the graft-versus-tumor effect mediated by alloreactive lymphocytes. Tumor vaccines are being explored as a therapeutic strategy to re-educate host immunity to recognize and target malignant cells through the activation and expansion of effector cell populations. Via several mechanisms, tumor cells induce T cell dysfunction and senescence, amplifying and maintaining tumor cell immunosuppressive effects, resulting in failure of clinical trials of tumor vaccines and adoptive T cell therapies. The fundamental premise of successful vaccine design involves the introduction of tumor-associated antigens in the context of effective antigen presentation so that tolerance can be reversed and a productive response can be generated. With the increasing understanding of the role of both the tumor and tumor microenvironment in fostering immune tolerance, vaccine therapy is being explored in the context of immunomodulatory therapies. The most effective strategy may be to use combination therapies such as anti-cancer vaccines with checkpoint blockade to target critical aspects of this environment in an effort to prevent the re-establishment of tumor tolerance while limiting toxicity associated with autoimmunity.

DCOne as an Allogeneic Cell-based Vaccine for Multiple Myeloma.

Multiple myeloma (MM) is characterized by progressive immune dysregulation, loss of myeloma-specific immunity, and an immunosuppressive milieu that fosters disease growth and immune escape. Accordingly, cancer vaccines that reverse tumor-associated immune suppression represent a promising therapeutic avenue of investigation. We examined the potential of an allogeneic cellular vaccine to generate immune responses against MM tumor cells. The DCOne vaccine is comprised of a human myeloid leukemia cell line differentiated into a fully functional dendritic cell, expressing a range of tumor-associated antigens that are also known targets in MM. We found that the myeloma-specific antigens expressed by the DCOne vaccine can traffic via extracellular vesicles to surrounding antigen-presenting cells, thus stimulating autologous T-cell responses. Indeed, coculture of peripheral blood mononuclear cells from patients with MM with the DCOne vaccine resulted in the expansion of activated CD8 T cells expressing interferon-γ and perforin, with no significant change in the percentage of CD4 T cells producing interleukin-10. Further, coculture of patient's tumor cells with peripheral blood mononuclear cells and DCOne induced cytotoxic T-lymphocyte-mediated killing of autologous MM cells. These findings demonstrate that the allogeneic DCOne vaccine can induce T-cell activation and myeloma-specific immunity via cross presentation of antigens by native antigen-presenting cells.

Challenges in vaccine therapy in hematological malignancies and strategies to overcome them.

INTRODUCTION: Hematological malignancies (HM) are a promising platform for immunotherapy when considering the marked durable remissions historically achieved through allogeneic stem cell transplantation in select patients. Both non-cell and cell-based vaccine models have been utilized to elicit T cell tumor-specific eradication of malignant cells with resultant striking immunologic effects, but only modest clinical outcomes. In the last decade, the field of oncology has garnered greater insight into the complex mechanisms underpinning immune dysregulation in HM. AREAS COVERED: This review addresses the development of vaccine strategies for HM examining the challenges of effectively inducing tumor-specific immunity and overcoming the barriers created by the tumor microenvironment. EXPERT OPINION: Through a better understanding of the tumor immunosuppressive milieu and immunobiology of HM, rational immunotherapeutic combination therapies can be designed incorporating the potency of vaccine therapy to stimulate native immune responses. In current practice, the use of combinatorial immunotherapies in the treatment of HM is becoming more recognized. This strategy, with vaccines as the backbone, will likely lead to paradigm-changing therapeutic regimens in the decades to come, affording HM patients with durable remissions and improved quality of life.