RESUMO
The effect of prior inotuzumab ozogamicin (InO) treatment on brexucabtagene autoleucel (brexu-cel) outcomes remains unclear in adults with acute lymphoblastic leukemia (ALL), particularly the influence off previous InO response and the timing of administration. We conducted a retrospective multicenter analysis of 189 patients with relapsed/refractory (r/r) ALL treated with brexu-cel. Over half of the patients received InO before brexu-cel (InO-exposed). InO-exposed patients were more heavily pretreated (p= 0.02) and frequently had active marrow disease pre-apheresis (p= 0.03). Response rate and toxicity profile following brexu-cel were comparable for InO-exposed and InO-naïve; however, consolidation therapy post brexu-cel response was utilized at a higher rate in InO-naïve patients (p= 0.005). With a median follow up of 11.4 months, InO-exposed patients had inferior progression-free survival (PFS) (p=0.013) and overall survival (OS) (p=0.006) in univariate analyses; however, prior InO exposure did not influence PFS (HR 1.20, 95%CI, 0.71-2.03) in multivariate models. When InO-exposed patients were stratified according to prior InO response, InO responders had superior PFS (p=0.002) and OS (p<0.0001) relative to InO-refractory. The timing of administering InO did not affect brexu-cel outcomes, with comparable PFS (p=0.51) and OS (p=0.86) for patients receiving InO as bridging therapy or pre-apheresis. In conclusion, while InO exposure was associated with inferior survival outcomes following brexu-cel in unadjusted analyses, these associations were no longer significant in multivariate analyses, suggesting it is unlikely that InO negatively impacts brexu-cel efficacy. Our data instead imply that InO-exposed recipients of brexu-cel tend to be higher-risk patients with intrinsic adverse leukemia biology.
RESUMO
Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce T cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a chimeric antigen receptor (CAR) targeting CD5, a prominent pan-T cell antigen, induces rapid internalization and complete loss of the CD5 protein on T cells, protecting them from self-targeting. Notably, exposure of healthy and malignant T cells to CD5.CART cells induces similar internalization of CD5 on target cells, transiently shielding them from cytotoxicity. However, this protection is short-lived, as sustained activity of CD5.CART cells in patients with T cell malignancies results in full ablation of CD5+ T cells while sparing healthy T cells naturally lacking CD5. These results indicate that continuous downmodulation of the target antigen in CD5.CART cells produces effective fratricide resistance without undermining their on-target cytotoxicity.
Assuntos
Antígenos CD5 , Receptores de Antígenos Quiméricos , Antígenos CD5/metabolismo , Humanos , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Citotoxicidade Imunológica , Linfócitos T/imunologia , Linfócitos T/metabolismo , Imunoterapia Adotiva/métodos , Animais , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
ABSTRACT: For patients with high-risk or relapsed/refractory acute myeloid leukemia (AML), allogeneic stem cell transplantation (allo-HSCT) and the graft-versus-leukemia effect mediated by donor T cells, offer the best chance of long-term remission. However, the concurrent transfer of alloreactive T cells can lead to graft-versus-host disease that is associated with transplant-related morbidity and mortality. Furthermore, â¼60% of patients will ultimately relapse after allo-HSCT, thus, underscoring the need for novel therapeutic strategies that are safe and effective. In this study, we explored the feasibility of immunotherapeutically targeting neoantigens, which arise from recurrent nonsynonymous mutations in AML and thus represent attractive targets because they are exclusively present on the tumor. Focusing on 14 recurrent driver mutations across 8 genes found in AML, we investigated their immunogenicity in 23 individuals with diverse HLA profiles. We demonstrate the immunogenicity of AML neoantigens, with 17 of 23 (74%) reactive donors screened mounting a response. The most immunodominant neoantigens were IDH2R140Q (n = 11 of 17 responders), IDH1R132H (n = 7 of 17), and FLT3D835Y (n = 6 of 17). In-depth studies of IDH2R140Q-specific T cells revealed the presence of reactive CD4+ and CD8+ T cells capable of recognizing distinct mutant-specific epitopes restricted to different HLA alleles. These neo-T cells could selectively recognize and kill HLA-matched AML targets endogenously expressing IDH2R140Q both in vitro and in vivo. Overall, our findings support the clinical translation of neoantigen-specific T cells to treat relapsed/refractory AML.
Assuntos
Antígenos de Neoplasias , Isocitrato Desidrogenase , Leucemia Mieloide Aguda , Humanos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Transplante de Células-Tronco Hematopoéticas , Imunoterapia/métodos , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , MutaçãoRESUMO
ABSTRACT: Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.
Assuntos
Imunoterapia Adotiva , Linfoma de Células T , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos T , Doença Crônica , Linfoma de Células T/tratamento farmacológico , Antígenos CD19RESUMO
The authors review the current use of chimeric antigen receptor (CAR)-transduced T cells (CAR-T) in Hodgkin lymphoma (HL) and T-cell lymphomas (TCL) and discuss the data on CD30-targeting CAR-T cells, which seem to be safe and effective in HL. In addition, the authors examine the use of CAR-T cells targeting CD30, CD5, or CD7 in TCL, while highlighting the unique challenges of their use in this subset of lymphomas. Furthermore, the authors present future directions and ongoing trials investigating the use of CAR-T cells in TCL and HL.
Assuntos
Doença de Hodgkin , Linfoma de Células T , Linfoma , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Antígeno Ki-1 , Doença de Hodgkin/terapia , Doença de Hodgkin/patologia , Linfócitos T , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7-, fratricide-resistant CD7 CAR T cells that were transcriptionally similar to control CD7-edited CD7 CAR T cells. Finally, we showed feasibility of cGMP manufacturing of unedited autologous CD7 CAR T cells for patients with CD7+ malignancies and initiated a phase I clinical trial (ClinicalTrials.gov: NCT03690011) using this approach. These results indicate pharmacologic inhibition of CAR signaling enables generating functional CD7 CAR T cells without additional engineering.
Assuntos
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Antígenos Quiméricos , Camundongos , Animais , Humanos , Linfócitos T , Imunoterapia Adotiva/métodos , Dasatinibe/metabolismo , Estudos de Viabilidade , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismoRESUMO
Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, 13 patients (3.8%) developed another cancer with a total of 16 events (4 hematologic malignancies and 12 solid tumors). The 5-year cumulative incidence of a first subsequent malignancy in the recipients of genetically modified IE cells was 3.6% (95% confidence interval, 1.8% to 6.4%). For 11 of the 16 subsequent tumors, biopsies were available, and no sample was transgene positive by polymerase chain reaction. Replication-competent retrovirus testing of peripheral blood mononuclear cells was negative in the 13 patients with subsequent malignancies tested. Rates of subsequent malignancy were low and comparable to standard chemotherapy. These results suggest that the administration of IE cells genetically modified with γ retroviral vectors does not increase the risk for subsequent malignancy.
Assuntos
Neoplasias Hematológicas , Neoplasias , Adulto , Criança , Seguimentos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Leucócitos Mononucleares , Neoplasias/genética , Neoplasias/terapia , Estudos RetrospectivosRESUMO
While high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) leads to improved disease-free survival (DFS) for children and adults with relapsed/refractory Hodgkin lymphoma (HL), relapse remains the most frequent cause of mortality post-transplant. Rituximab has been successfully incorporated into regimens for other B-cell lymphomas, yet there have been limited studies of rituximab in HL patients. We hypothesized that adding rituximab to BEAM (carmustine, etoposide, cytarabine, melphalan) conditioning would reduce relapse risk in HL patients post-transplant. Here, we retrospectively review the outcomes of patients with relapsed/refractory HL who received rituximab in addition to BEAM. The primary outcome was DFS. Our cohort included 96 patients with a median age of 28 years (range, 6-76). Majority of patients (57%) were diagnosed with advanced (Stage III-IV) disease, and 62% were PET negative pre-transplant. DFS was 91.5% at 1 year [95% CI 86-98%], and 78% at 3 years [95% CI 68-88%]. NRM was 0% and 3.5% at 1-year [95% CI 0-3%] and 3-years [95% CI 0-8.5%], respectively. 25% of patients developed delayed neutropenia, with 7% requiring infection-related hospitalizations, and one death. We have demonstrated excellent outcomes for patients receiving rituximab with BEAM conditioning for relapsed/refractory HL. Future comparative studies are needed to better determine whether rituximab augments outcomes post-transplant.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Carmustina/uso terapêutico , Criança , Citarabina , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Melfalan , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Rituximab/uso terapêutico , Condicionamento Pré-Transplante , Transplante Autólogo , Adulto JovemRESUMO
Adoptive transfer of CD19-specific chimeric antigen receptor T-cells (CAR-T cells) has transformed the treatment paradigm of relapsed/refractory (R/R) CD19 B-cell malignancies, dramatically improving remission rates and cures in patients with chemo-refractory disease. However, the applicability of CD19 CAR-T cells is limited to B cell malignancies and antigen loss can result in treatment failure, prompting the exploration of alternative targets to overcome tumor escape via CD19 antigen loss, as well as extend the CAR-T cell platform to treat Hodgkin and T cell lymphomas. This review highlights recent clinical trials testing CAR-T cell targets beyond CD19.
Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Linfoma , Receptores de Antígenos Quiméricos , Antígenos CD19/imunologia , Humanos , Linfoma/imunologia , Linfoma/terapia , Recidiva Local de Neoplasia/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/transplanteRESUMO
Hispanics and non-Hispanic (NH)-Blacks continue to face numerous health disparities related to multiple myeloma (MM). We aimed to analyze trends of MM-related hospitalizations and incidence of in-hospital mortality with a 10-year cross-sectional analysis of inpatient hospitalizations. The prevalence of MM-related hospitalizations was higher in NH-Blacks compared to NH-Whites (476.0 vs. 305.6 per 100,000 hospitalizations, p < .001). MM-related in-hospital mortality was higher in Hispanics compared to NH-Whites and NH-Blacks (6.2 vs. 5.3%, p < .001). Using average annual percent change (AAPC), we found a statistically significant decline of in-hospital mortality among all MM patients except NH-Blacks (AAPC: -2.2, 95% confidence interval (CI) -4.7, 0.4, p = .47), who had the highest inpatient mortality in recent years. Multivariate analysis showed that NH-Blacks received fewer transplants, more blood product transfusions, fewer palliative care consults, less inpatient chemotherapy, and utilized more intensive care. Disparities in MM care for NH-Blacks and Hispanics continue to persist despite recent advancements in MM therapy.
Assuntos
Mieloma Múltiplo , Negro ou Afro-Americano , Estudos Transversais , Hispânico ou Latino , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/terapia , Estados Unidos/epidemiologia , População BrancaRESUMO
Resistance to conventional lines of therapy develops in approximately 20% of all patients with lymphoma. These patients have a dismal prognosis, with an expected median survival of 6.3 months. In recent years, T-cell immunotherapy has demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphoma. A major contributor to the success of immunotherapy has been the advent of genetic engineering technologies that introduce a chimeric antigen receptor (CAR) into T cells to focus their killing activity on tumor cells. The adoptive transfer of autologous CAR T-cell products specific for the pan-B-cell antigen CD19 have now received approval from the US Food and Drug Administration (FDA) for the treatment of relapsed or chemotherapy-resistant B-cell non-Hodgkin lymphoma. This review is designed to showcase the clinical efficacy and unique toxicities of individually developed CAR T-cell products for the treatment of lymphomas and their evolution from the laboratory bench to commercialization.