scholarly journals Hematopoeitic Cell Transplantation and CAR T-Cell Therapy: Complements or Competitors?

2020 ◽  
Vol 10 ◽  
Author(s):  
Scott R. Goldsmith ◽  
Armin Ghobadi ◽  
John F. DiPersio
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
Cellular Immunotherapy ◽  
T Cell Therapy ◽  
Car T ◽  
History Of ◽  
B Lymphoid

Allogeneic hematopoietic cell transplantation (allo-HCT) and chimeric antigen receptor T cell (CAR T) therapy are the main modalities of adoptive cellular immunotherapy that have widely permeated the clinical space. The advent of both technologies revolutionized treatment of many hematologic malignancies, both offering the chance at sustained remissions for patients who would otherwise invariably succumb to their diseases. The understanding and exploitation of the nonspecific alloreactivity of allo-HCT and the graft-versus-tumor effect is contrasted by the genetically engineered precision of CAR T therapy. Historically, those with relapsed and refractory hematologic malignancies have often been considered for allo-HCT, although outcomes vary dramatically and are associated with potential acute and chronic toxicities. Such patients, mainly with B-lymphoid malignancies, may now be offered CAR T therapy. Yet, a lack of prospective data to guide decisions thereafter requires individualized approaches on whether to proceed to allo-HCT or observe. The continued innovations to make CAR T therapy more effective and accessible will continue to alter such approaches, but similar innovations in allo-HCT will likely result in similarly improved clinical outcomes. In this review, we describe the history of the two platforms, dissect the clinical indications emphasizing their intertwining and competitive roles described in trials and practice guidelines, and highlight innovations in which they complement or inform one another.

scholarly journals Strengthening the CAR-T Cell Therapeutic Application using CRISPR/Cas9 Technology

2021 ◽  
Author(s):  
Muhammad Sadeqi Nezhad ◽  
Mahboubeh Yazdanifar ◽  
Meghdad Abdollahpour-Alitappeh ◽  
Arash Sattari ◽  
Alexander seifalian ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Side Effects ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Promising Tool ◽  
Car T

Adoptive cell immunotherapy with chimeric antigen receptor (CAR) T cell has brought a revolutionary means of treatment for aggressive diseases such as hematologic malignancies and solid tumors. Over the last decade, FDA approved three types of CAR-T cells against CD19 hematologic malignancies, including Tisagenlecleucel (Kymriah), Axicabtagene ciloleucel (Yescarta), and Brexucabtagene autoleucel (Tecartus). Despite outstanding results gained from different clinical trials, CAR-T cell therapy is not free from side effects and toxicities, and needs careful investigations and improvements. Gene-editing technology, clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR-associated protein 9 (Cas9) system has emerged as a promising tool to address some of the CAR-T therapy hurdles. Using CRISPR/Cas9 technology, CAR expression as well as other cellular pathways can be modified in various ways to enhance CAR-T cell’s anti-tumor function and persistence in immunosuppressive tumor microenvironment. CRISPR/Cas9 technology can also be utilized to reduce CAR-T cells toxicity and side effects. Hereby, we discuss the practical challenges and hurdles related to the accuracy, efficiency, efficacy, safety and delivery of CRISPR/Cas9 technology to the genetically engineered-T cells. Combining of these two state-of-the-art technologies, CRISPR/Cas9 and CAR-T cells, the field of oncology has an extraordinary opportunity to enter a new era of immunotherapy, which offers novel therapeutic options for different types of tumors.

scholarly journals Encouraging Survival and High Rates of Toxicity: Allogeneic Hematopoietic Cell Transplantation after Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy in Aggressive Lymphoma Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 910-910
Author(s):  
Shalev Fried ◽  
Ivetta Danylesko ◽  
Ronit Yerushalmi ◽  
Noga Shem-Tov ◽  
Roni Shouval ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Aggressive Lymphoma ◽  
T Cell Therapy ◽  
Car T

Abstract Background Approximately 60% of patients with aggressive large B-cell lymphoma (ALBCL) treated with anti-CD19 chimeric antigen receptor T-cell (CAR T) will ultimately progress or relapse. Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for lymphoma patients who relapse after CAR T-cell therapy. However, the efficacy and toxicity profile of allo-HCT following CAR T in aggressive lymphoma patients are not well defined. Herein, we report our experience. Methods and patients A total of 29 adult patients (median age 45 years [IQR 40-55]) who received allo-HCT for ALBCL between 2017 to 2021 were included. All patients were previously treated with anti-CD19 CAR T-cell (academic CD28-costimulatory domain product [n=23, 79%]; tisagenlecleucel [n=6, 21%]). Twenty-five (86%) and 4 (14%) had a diagnosis of DLBCL and PMBCL, respectively. Median number of previous therapies before CAR T was 3 (IQR 2-4). Eight (28%) patients underwent a previous autologous HCT. No patient underwent a previous allo-HCT. Median hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was 3 (IQR 2-3). Six (21%) patients had a Karnofsky performance status ≤ 80%. Allo-HCT was performed at a median of 4.1 months (IQR 2.2-5.4) post CAR T, with the majority of patients (48%) receiving transplant as first-line post CAR T. Reasons for allo-HCT were consolidation of complete response (CR) to CAR T in high-risk disease (n=4, 14 %), partial response (PR) to CAR T (n=7, 24%) and relapse /progression after CAR T (n=18, 62%). Disease response before allo-HCT was CR (n=11, 38%), PR (n=11, 38%) and progressive disease (n=7, 24%). Donors were matched siblings (n=13, 45%), matched unrelated (n=9, 31%) and mismatched unrelated /haploidentical donors (n=7, 24%). Myeloablative and reduced-intensity conditioning regimens were given in 13 (45%) and 16 (55%) patients, respectively. Methotrexate-based graft versus host disease (GVHD) prophylaxis was used in 20 (69%) patients. Antithymocyte globulin and post-transplantation cyclophosphamide were administered in 13 (45%) and 5 (14%), respectively. Results Median follow-up was 33 months (IQR 13-41). Neutrophil engraftment rate was 93% (two early deaths before engraftment due to infection and multi-organ failure). Two-year overall survival (OS) and progression-free survival were 44% (95% CI: 28-68) and 30% (95% CI: 17-55), respectively. Two-year cumulative relapse incidence and non-relapse mortality were 45% (95% CI: 25-63) and 25% (95% CI: 11-43), respectively (Figure). In a univariable Cox regression, factors significantly associated with a shorter OS were number of interim therapies between CAR T and allo-HCT (Hazard ratio [HR] 2.2 [95% CI: 1.3-3.9], p 0.006) and the length of time between CAR T and allo-HCT (HR 3.8 [95% CI: 1.2-12.1], p 0.02). Best response to CAR T and disease response before allo-HCT were not significant risk factors for a shorter OS. High rates of grade ≥ 3 hyperbilirubinemia (total bilirubin >3 ULN) and hepatic sinusoidal obstruction syndrome (SOS) were observed in 10 (35%) and 5 (17%) patients, respectively. These liver insults were not contributed to acute GVHD. All patients with SOS were treated with defibrotide and two patients died from related complications. Interestingly, 4/5 patients with SOS were conditioned with fludarabine and thiotepa. One-year cumulative incidence of grade II-IV acute GVHD was 34% (n=10; 95% CI: 18-52). Notably, 6 patients had grade IV acute GVHD, 4 of them were refractory to corticosteroids and 3 patients died due to acute GVHD. Two-year cumulative incidence of chronic GVHD was 23% (n=5; 95% CI: 7-46). Chronic GVHD was considered extensive in 4 of them. Bloodstream bacterial infection was documented in 11 (38%) patients. Invasive fungal infection occurred in 6 (21%) patients and included brain aspergillosis, cutaneous aspergillosis, 2 lung aspergillosis, hepatosplenic candidiasis and an ocular mucor mycosis. Conclusion Allogeneic hematopoietic cell transplantation is feasible after failure of CAR T-cell therapy in aggressive lymphoma, although with a relatively high rate of SOS and severe acute GVHD in these heavily pretreated patients. Overall survival is encouraging with approximately 30% of patients remaining alive and disease-free at two years. Larger scale studies are required to better define the role of allo-HCT in this setting. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Jacoby: NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Avigdor: Takeda: Consultancy, Honoraria; Janssen: Research Funding; BMS: Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

scholarly journals Unexpected neurologic complications following a novel lymphoma treatment ‘expected’ to give rise to neurologic toxicity

2019 ◽  
Vol 12 (11) ◽  
pp. e229946 ◽  
Author(s):  
Marie José Kersten ◽  
Cornelis N van Ettekoven ◽  
Dianne M Heijink
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Sinus Thrombosis ◽  
Genetically Engineered ◽  
Cellular Immunotherapy ◽  
T Cell Therapy ◽  
Neurologic Symptoms ◽  
Car T Cell ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy is a novel and promising form of cellular immunotherapy using genetically engineered, tumour-specific autologous T cells. CD19-specific CAR T-cells have been shown to be very effective as a treatment for relapsed/refractory B-cell acute lymphoblastic leukaemia and aggressive B-cell non-Hodgkin’s lymphoma. ICANS (immune effector cell-associated neurotoxicity syndrome) is one of the most frequently occurring toxicities of CAR T-cell treatment. We describe two cases of patients with neurologic symptoms following CAR T-cell infusion who were suspected to have ICANS, but in fact had cerebral toxoplasmosis and venous sinus thrombosis respectively. The focus on CRS and ICANS after CAR T-cell infusion may lead to less vigilance to the ‘normal’ threats faced by intensively pretreated patients with lymphoma such as infections and thrombosis. Both cases underscore the importance of a broad and thorough examination of patients if they experience neurologic symptoms after CAR T-cell treatment.

scholarly journals Response to SARS-CoV-2 vaccination in patients after hematopoietic cell transplantation and CAR-T cell therapy

Blood ◽  
2021 ◽  
Author(s):  
Binod Dhakal ◽  
Sameem M Abedin ◽  
Timothy S. Fenske ◽  
Saurabh Chhabra ◽  
Nathan Ledeboer ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy

2020 ◽  
Vol 55 (11) ◽  
pp. 2071-2076 ◽  
Author(s):  
Per Ljungman ◽  
◽  
Malgorzata Mikulska ◽  
Rafael de la Camara ◽  
Grzegorz W. Basak ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Cellular Therapy ◽  
Working Party ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

Abstract The new coronavirus SARS-CoV-2 has rapidly spread over the world causing the disease by WHO called COVID-19. This pandemic poses unprecedented stress on the health care system including programs performing allogeneic and autologous hematopoietic cell transplantation (HCT) and cellular therapy such as with CAR T cells. Risk factors for severe disease include age and predisposing conditions such as cancer. The true impact on stem cell transplant and CAR T-cell recipients in unknown. The European Society for Blood and Marrow Transplantation (EBMT) has therefore developed recommendations for transplant programs and physicians caring for these patients. These guidelines were developed by experts from the Infectious Diseases Working Party and have been endorsed by EBMT’s scientific council and board. This work intends to provide guidelines for transplant centers, management of transplant candidates and recipients, and donor issues until the COVID-19 pandemic has passed.

The Other Side of CAR T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden

2019 ◽  
pp. 433-444 ◽  
Author(s):  
Bianca Santomasso ◽  
Carlos Bachier ◽  
Jason Westin ◽  
Katayoun Rezvani ◽  
Elizabeth J. Shpall
Keyword(s):  
T Cells ◽  
T Cell ◽  
Financial Burden ◽  
Hematologic Malignancies ◽  
Genetically Engineered ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Effector Cells ◽  
Car T Cell ◽  
Car T

Immune effector cells, including T cells and natural killer cells, which are genetically engineered to express a chimeric antigen receptor (CAR), constitute a powerful new class of therapeutic agents to treat patients with hematologic malignancies. Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity. With more experience and collaboration, hopefully the toxicities and the costs will come down, increasing the availability of CAR T cells to patients in need.

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