scholarly journals Double-refractory Hodgkin lymphoma: tackling relapse after brentuximab vedotin and checkpoint inhibitors

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 247-253
Author(s):  
Narendranath Epperla ◽  
Mehdi Hamadani
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cellular Therapy ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Killer Cell ◽  
Brentuximab Vedotin ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract The approval of brentuximab vedotin (BV) and checkpoint inhibitors (CPI) has revolutionized the management of relapsed/refractory classical Hodgkin lymphoma (cHL) patients. In recent years these agents have rapidly moved to earlier lines of therapy, including post-autologous hematopoietic cell transplant (auto-HCT) consolidation, pre-HCT salvage, and the frontline treatment setting. This shift in practice means that double-refractory (refractory to both BV and CPI) cHL is becoming an increasingly common clinical problem. In patients who are not eligible for clinical trials, conventional cytotoxic and targeted therapies (off label) may be a potential option. In patients who are transplant eligible, early referral to allogeneic HCT should be considered given the significant improvement in transplant outcomes in the contemporary era. Cellular therapy options including CD30.chimeric antigen receptor T cells, Epstein-Barr virus-directed cytotoxic T cells, and CD16A/30 bispecific natural killer cell engagers appear promising and are currently in clinical trials.

scholarly journals Novel agents and immune invasion in Hodgkin lymphoma

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 243-248 ◽  
Author(s):  
Reid W. Merryman ◽  
Ann LaCasce
Keyword(s):  
T Cells ◽  
Hodgkin Lymphoma ◽  
Cytotoxic T Cells ◽  
Rapid Development ◽  
Predictive Biomarkers ◽  
Treatment Resistance ◽  
Brentuximab Vedotin ◽  
Antibody Drug Conjugate ◽  
Barr Virus ◽  
Epstein Barr

Abstract The approval of brentuximab vedotin (BV) and the PD-1 inhibitors nivolumab and pembrolizumab has dramatically improved outcomes for patients with relapsed or refractory (R/R) classic Hodgkin lymphoma (HL). With the goal of increasing long-term disease control rates and decreasing late toxicities, these agents are currently being tested in earlier phases of treatment in combination with chemotherapy agents. In the R/R setting, our expanding understanding of HL’s various mechanisms of immune evasion and treatment resistance has spurred a growing number of rationally designed combination trials. Beyond BV and PD-1 blockade, other novel therapies have demonstrated encouraging preliminary results, including targeted agents, like the CD25 antibody-drug conjugate ADCT-301, and cellular therapies, including CD30 chimeric antigen receptor T cells and Epstein-Barr virus (EBV)-directed cytotoxic T cells. These trials, coupled with the rapid development of prognostic and predictive biomarkers, should drive additional breakthroughs that promise safer and more effective therapies for patients with HL in the future.

Brentuximab vedotin as consolidation after hematopoietic cell transplant for relapsed Hodgkin lymphoma in pediatric patients

2019 ◽  
Vol 66 (12) ◽  
Author(s):  
Jamie E. Flerlage ◽  
Xinyu Buttlar ◽  
Matthew Krasin ◽  
Brandon Triplett ◽  
Sue C. Kaste ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Pediatric Patients ◽  
Brentuximab Vedotin ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Inhibitory Effect of PD-1/PD-L1 and Blockade Immunotherapy in Leukemia

2021 ◽  
Vol 24 ◽  
Author(s):  
Kai Xing ◽  
Pan Zhou ◽  
Jiaojiao Li ◽  
Miao Liu ◽  
Wei Emma Zhang
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Solid Tumors ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Inhibitory Effect ◽  
Main Body ◽  
Intracellular Signals ◽  
Effect Of Pd

Background: PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of a variety of solid tumors. And some clinical trials have also confirmed the excellent efficacy of PD-1/PD-L1 inhibitors on lymphoma. However, the efficacy of PD-1/PD-L1 inhibitors on leukemia remains unclear. Main body: To understand the connection between PD-1/PD-L1 and leukemia better, this review concentrates on the up-regulated expression of PD-1/PD-L1 and the PD-1/PD-L1 blockade trials in participants with leukemia. PD-1/PD-L1 signal performs momentously negative immunoregulation of cancer, which can inhibit the activation of cytotoxic T cells and involve in the immune escape in tumors. Activated PD-1/PD-L1 may transduce negative intracellular signals to block the mitotic cycle and the development of T-cells. Several pathways are involved in these critical biochemical processes, including MAPK, Calcium, PI3K/AKT, and so on. Lately, PD-1/PD-L1 antibodies have illustrated unprecedented curative effects in the field of Hodgkin's lymphoma and some solid tumors. Specimens from patients with leukemia demonstrated the elevated level of PD-1/PD-L1 in T lymphocytes. This finding inspired hematologists to use PD-1/PD-L1 inhibitors for subjects suffering from leukemia. Some clinical trials implied that PD-1/PD-L1 inhibitors could help patients fight against leukemia. However, other researchers reported the opposite results. Conclusions: PD-1/PD-L1 is upregulated in leukemia, but the results regarding PD-1/PD-L1 blockade are mixed and more clinical trials are needed to be conducted.

scholarly journals Novel agents and strategies in transplant-eligible patients with relapsed and refractory Hodgkin lymphoma

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 331-338 ◽  
Author(s):  
Craig Moskowitz
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Brentuximab Vedotin ◽  
Novel Agents ◽  
Cell Transplant ◽  
Antibody Drug Conjugate ◽  
Early Stage Disease ◽  
Treatment Paradigm

Abstract The majority of patients with Hodgkin lymphoma are cured with frontline therapy; however, 10% to 15% with early-stage disease and 20% to 30% with advanced stage require second-line therapy that includes a potentially curative transplant, of which an additional 50% to 55% are cured. Those with multiply relapsed disease traditionally would receive novel agents on a clinical trial or combination chemotherapy as a potential bridge to an allogeneic stem cell transplant. This treatment paradigm has changed with the availability of brentuximab vedotin, an antibody drug conjugate used pre- and post-ASCT, as well as for palliation. With the availability of the checkpoint inhibitors, nivolumab and pembrolizumab, there will be another shift in treatment, with these agents being used for palliation and potentially replacing allogeneic stem cell transplantation in certain patient populations. Finally, up-front management is also changing and this will have an impact on how patients in the relapsed and refractory setting will be treated.

scholarly journals Transplant strategies in relapsed/refractory Hodgkin lymphoma

Blood ◽  
2018 ◽  
Vol 131 (15) ◽  
pp. 1689-1697 ◽  
Author(s):  
Gunjan L. Shah ◽  
Craig H. Moskowitz
Keyword(s):  
Side Effects ◽  
Hodgkin Lymphoma ◽  
Checkpoint Inhibitors ◽  
Remission Rate ◽  
Therapeutic Option ◽  
Response Rates ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract The majority of patients with Hodgkin lymphoma (HL) are cured with initial therapy. However, high-dose therapy with autologous hematopoietic cell transplant (AHCT) allows for the cure of an additional portion of patients with relapsed or primary refractory disease. Positron emission tomography–negative complete remission before AHCT is critical for long-term disease control. Several salvage options are available with comparable response rates, and the choice can be dependent of comorbidities and logistics. Radiation therapy can also improve the remission rate and is an important therapeutic option for selected patients. Brentuximab vedotin (BV) maintenance after AHCT is beneficial in patients at high risk for relapse, especially those with more than 1 risk factor, but can have the possibility of significant side effects, primarily neuropathy. Newer agents with novel mechanisms of action are under investigation to improve response rates for patients with subsequent relapse, although are not curative alone. BV and the checkpoint inhibitors nivolumab and pembrolizumab are very effective with limited side effects and can bridge patients to curative allogeneic transplants (allo-HCT). Consideration for immune-mediated toxicities, timing of allogeneic hematopoietic cell transplant based on response, and the potential for increased graft-versus-host disease remain important. Overall, prospective investigations continue to improve outcomes and minimize toxicity for relapsed or primary refractory HL patients.

scholarly journals How to choose first salvage therapy in Hodgkin lymphoma: traditional chemotherapy vs novel agents

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 240-246
Author(s):  
Julia Driessen ◽  
Sanne H. Tonino ◽  
Alison J. Moskowitz ◽  
Marie José Kersten
Keyword(s):  
Clinical Trials ◽  
Hodgkin Lymphoma ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
New Drugs ◽  
High Dose ◽  
Cell Transplant ◽  
Novel Therapies ◽  
The Past

Abstract Approximately 10% to 30% of patients with classical Hodgkin lymphoma (cHL) develop relapsed or refractory (R/R) disease. Of those patients, 50% to 60% show long-term progression-free survival after standard salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). In the past decade, novel therapies have been developed, such as the CD30-directed antibody–drug conjugate brentuximab vedotin and immune checkpoint inhibitors, which have greatly extended the treatment possibilities for patients with R/R cHL. Several phase 1/2 clinical trials have shown promising results of these new drugs as monotherapy or in combination with chemotherapy, but unfortunately, very few randomized phase 3 trials have been performed in this setting, making it difficult to give evidence-based recommendations for optimal treatment sequencing. Two important goals for the improvement in the treatment of R/R cHL can be identified: (1) increasing long-term progression-free and overall survival by optimizing risk-adapted treatment and (2) decreasing toxicity in patients with a low risk of relapse of disease by evaluating the need for HDCT/ASCT in these patients. In this review, we discuss treatment options for patients with R/R cHL in different settings: patients with a first relapse, primary refractory disease, and in patients who are ineligible or unfit for ASCT. Results of clinical trials investigating novel therapies or strategies published over the past 5 years are summarized.

scholarly journals Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients

2021 ◽  
Author(s):  
Kent P Jensen ◽  
David Hongo ◽  
Xuhuai Ji ◽  
Pingping Zheng ◽  
Rahul D Pawar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Conditioning Regimen ◽  
Myeloid Cells ◽  
Hematopoietic Cell ◽  
Mixed Chimerism ◽  
Solid Organ ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Post Transplant

Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs have long been the goals of organ transplantation. We studied changes in the balance of T and myeloid cells in blood of HLA-matched and -mismatched patients given living donor kidney transplants (KTx) followed by total lymphoid irradiation (TLI), anti-thymocyte globulin (ATG) conditioning, and donor hematopoietic cell transplant (HCT) to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In pre-clinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive, polymorphonuclear (pmn), myeloid derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of the pmn-MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes including profound depletion of T cells and a marked increase in MDSCs in blood post-transplant. Post-transplant pmn-MDSCs transiently increased expression of lectin-type, oxidized LDL receptor-1 (LOX-1), a marker of immunosuppression, and production of the T cell inhibitor, arginase-1. These post-transplant pmn-MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous, TCR microbead-stimulated, pre-transplant T cells when co-cultured in vitro. In conclusion, we elucidated changes in receptors, and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to the that of MDSCs required for tolerance in mice. The clinical trials are registered in Clinicaltrials.gov under NCT #s 00319657 and 01165762.

scholarly journals Management of Herpesvirus Infections in Hematopoietic Cell Transplant Recipients

2021 ◽  
Vol 2 (1) ◽  
pp. 8-21
Author(s):  
Jan Styczynski
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cellular Therapy ◽  
Hematopoietic Cell ◽  
Host Cells ◽  
Preventive Strategy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant ◽  
Screening Assay ◽  
Specific Level

Following primary infection, herpesviruses establish latency in infected individuals in the host cells and may reactivate upon external stimuli and during periods of immunosuppression. The objective of this paper was to the present current strategies on preventive and therapeutic management of infections with herpesviruses in recipients of hematopoietic cell transplantation. Strategies of antiviral management include prophylaxis, pre-emptive treatment and targeted treatment. Empirical therapy is not used in antiviral strategies. Prophylaxis can be done at universal (preventive strategy) and specific level. Universal prophylaxis includes non-pharmacologic methods of prevention of infection or reactivation. Risk-adapted specific prophylaxis includes use of specific antivirals or cellular therapy or other specific methods in order to prevent specific infection, in high-risk groups. Pre-emptive therapy means use of therapeutic approaches in asymptomatic infection, detected by a screening assay. Targeted therapy is used in established specific viral end-organ infections. The following sections of the paper refer to prophylaxis and treatment strategies, respectively, against CMV, EBV, HSV, VZV, HHV-6, HHV-7, and HHV-8 after allogeneic hematopoietic cell transplantation.

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

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