Im A, Rashidi A, Wang T, Hemmer M, MacMillan ML, Pidala J, Jagasia M, Pavletic S, Majhail NS, Weisdorf D, Abdel-Azim H, Agrawal V, Al-Homsi AS, Aljurf M, Askar M, Auletta JJ, Bashey A, Beitinjaneh A, Bhatt VR, Byrne M, Cahn JY, Cairo M, Castillo P, Cerny J, Chhabra S, Choe H, Ciurea S, Daly A, Perez MAD, Farhadfar N, Gadalla SM, Gale R, Ganguly S, Gergis U, Hanna R, Hematti P, Herzig R, Hildebrandt GC, Lad DP, Lee C, Lehmann L, Lekakis L, Kamble RT, Kharfan-Dabaja MA, Khandelwal P, Martino R, Murthy HS, Nishihori T, O'Brien TA, Olsson RF, Patel SS, Perales MA, Prestidge T, Qayed M, Romee R, Schoemans H, Seo S, Sharma A, Solh M, Strair R, Teshima T, Urbano-Ispizua A, Van der Poel M, Vij R, Wagner JL, William B, Wirk B, Yared JA, Spellman SR, Arora M, Hamilton BK
Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.
Biol. Blood Marrow Transplant.17 May 2020, . Epub 17 May 2020
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with relatively low incidence of GVHD. Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haploHCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with AML, ALL, MDS, or CML who underwent PTCy-based haploHCT (2013-2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced intensity (RIC) conditioning and bone marrow (BM) or peripheral blood (PB) graft source. 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2-4 aGVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (p=0.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (p<0.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2-4 acute GVHD; however, older donor age (30-49 versus <29 years) was significantly associated with higher rates of grade 2-4 acute GVHD (HR 1.53, 95% CI 1.11-2.12, p=0.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR 1.70, 95% CI 1.11-2.62, p=0.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haploHCT. Our results indicate that in RIC haploHCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.
Perez-Amill L, Suñe G, Antoñana-Vildosola A, Castella M, Najjar A, Bonet J, Fernández-Fuentes N, Inogés S, López A, Bueno C, Juan M, Urbano-Ispizua A, Martín-Antonio B
Preclinical development of a humanized chimeric antigen receptor against B cell maturation antigen for multiple myeloma.
Haematologica9 Jan 2020, . Epub 9 Jan 2020
Multiple myeloma is a prevalent and incurable disease, despite the development of new and effective drugs. The recent development of chimeric antigen receptor (CAR)-T cell therapy has shown impressive results in the treatment of patients with relapsed or refractory hematological B cell malignancies. In the recent years, B-cell maturation antigen (BCMA) has appeared as a promising antigen to target using a variety of immuno-therapy treatments including CART cells, for MM patients. To this end, we generated clinical-grade murine CART cells directed against BCMA, named ARI2m cells. Having demonstrated its efficacy, and in an at-tempt to avoid the immune rejection of CART cells by the patient, the single chain variable fragment was humanized, creating ARI2h cells. ARI2h cells demonstrated comparable in vitro and in vivo efficacy to ARI2m cells, and superiority in cases of high tumor burden disease. In terms of inflammatory response, ARI2h cells showed a lower TNFα production and lower in vivo toxicity profile. Large-scale expansion of both ARI2m and ARI2h cells was efficiently conducted following Good Manufacturing Practice guidelines, obtaining the target CART cell dose required for treatment of multiple myeloma patients. Moreover, we demonstrate that soluble BCMA and BCMA released in vesicles impacts on CAR-BCMA activity. In sum-mary, this study sets the bases for the implementation of a clinical trial (EudraCT code: 2019-001472-11) to study the efficacy of ARI2h cell treatment for multiple myeloma patients.
Martín-Antonio B, Suñe G, Najjar A, Perez-Amill L, Antoñana-Vildosola A, Castella M, León S, Velasco-de Andrés M, Lozano F, Lozano E, Bueno C, Estanyol JM, Muñoz-Pinedo C, Robinson SN
Extracellular NK histones promote immune cell anti-tumor activity by inducing cell clusters through binding to CD138 receptor.
J Immunother Cancer16 Oct 2019, 7(1)259. Epub 16 Oct 2019
Natural killer (NK) cells are important anti-tumor cells of our innate immune system. Their anti-cancer activity is mediated through interaction of a wide array of activating and inhibitory receptors with their ligands on tumor cells. After activation, NK cells also secrete a variety of pro-inflammatory molecules that contribute to the final immune response by modulating other innate and adaptive immune cells. In this regard, external proteins from NK cell secretome and the mechanisms by which they mediate these responses are poorly defined.
Diagnosis of gastrointestinal (GI) cytomegalovirus (CMV) disease relies on the presence of GI symptoms and detection of CMV, mainly by immunohistochemistry (IHC), in GI biopsy specimens. Thus, in a symptomatic patient, a positive CMV-IHC result is accepted as a diagnosis of CMV disease. However, a positive CMV-PCR in GI tissue is considered "possible" CMV disease. Therefore, it would be very useful if, in practice, both techniques showed equal sensitivity and reliability. This is because PCR has many practical advantages over IHC for detecting CMV. The aim of this study was to compare quantitative PCR with IHC for the diagnosis of GI CMV disease. A total of 186 endoscopic GI biopsy specimens from 123 patients with GI symptoms after an allogeneic stem cell transplantation (allo-SCT; 2004-2017) were analyzed by IHC and PCR on 113 paraffin-embedded and 73 fresh samples. The results were then compared. Of the patients with macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, "proven" CMV disease, n = 28), all but 1 were CMV-PCR positive. Of the patients without macroscopic lesions in the mucosa and CMV-IHC-positive biopsy specimens (eg, probable CMV disease, n = 4), only 1 was CMV-PCR positive. Eight patients had CMV-IHC-negative/CMV-PCR-positive gut biopsy specimens. These cases fall within the current definition of possible CMV disease. In 6 of these 8 cases (75%), the viral load in GI tissue was very high (>10,000 copies/µg). Taken together, the results from the proven and probable cases revealed that CMV-PCR shows the same sensitivity (100%), specificity (98%), and positive (93%) and negative predictive value (100%) as CMV-IHC. Detection of CMV in fresh GI mucosa by quantitative PCR is as useful as IHC for the diagnosis of GI CMV disease. The results show that quantitative PCR has the same sensitivity, specificity, and positive/negative predictive value as IHC.
Castella M, Boronat A, Martín-Ibáñez R, Rodríguez V, Suñé G, Caballero M, Marzal B, Pérez-Amill L, Martín-Antonio B, Castaño J, Bueno C, Balagué O, González-Navarro EA, Serra-Pages C, Engel P, Vilella R, Benitez-Ribas D, Ortiz-Maldonado V, Cid J, Tabera J, Canals JM, Lozano M, Baumann T, Vilarrodona A, Trias E, Campo E, Menendez P, Urbano-Ispizua Á, Yagüe J, Pérez-Galán P, Rives S, Delgado J, Juan M
Development of a Novel Anti-CD19 Chimeric Antigen Receptor: A Paradigm for an Affordable CAR T Cell Production at Academic Institutions.
Mol Ther Methods Clin Dev15 Mar 2019, 12134-144. Epub 6 Dec 2018
Genetically modifying autologous T cells to express an anti-CD19 chimeric antigen receptor (CAR) has shown impressive response rates for the treatment of CD19+ B cell malignancies in several clinical trials (CTs). Making this treatment available to our patients prompted us to develop a novel CART19 based on our own anti-CD19 antibody (A3B1), followed by CD8 hinge and transmembrane region, 4-1BB- and CD3z-signaling domains. We show that A3B1 CAR T cells are highly cytotoxic and specific against CD19+ cells
Perez-Amill L, Marzal B, Urbano-Ispizua A, Juan M, Martín-Antonio B
CAR-T Cell Therapy: A Door Is Open to Find Innumerable Possibilities of Treatments for Cancer Patients
Turk J Haematol13 Nov 2018, 35(4)217-228. Epub 6 Sep 2018
Seven years ago a chronic lymphocytic leukemia patient was for the first time successfully treated with chimeric antigen receptor (CAR)-modified T cells (CAR-T cells) to target CD19 overexpression in tumor cells. This was the beginning of the development of a new type of immunotherapy treatment in cancer patients. Since then, identification of novel antigens expressed in tumor cells and optimization of both CAR constructs and protocols of administration have opened up new avenues for the successful treatment of other hematological malignancies. However, research still continues to avoid some problems such as toxicities associated with the treatment and to find strategies to avoid tumor cell immune evasion mechanisms. On the other hand, for solid tumors, CAR-T therapy results are still in an early phase. In contrast to hematological malignancies, the complex tumor heterogeneity of solid tumors has led to the research of novel and challenging strategies to improve CAR-T cell activity. Here, we will review the main clinical results obtained with CAR-T cells in hematological malignancies, specifically focusing on CAR-T-19 and CAR-T against B-cell maturation antigen (CAR-T-BCMA). Moreover, we will mention the main problems that decrease CAR-T cell activity in solid tumors and the strategies to overcome them. Finally, we will present some of the first clinical results obtained for solid tumors.
Martínez-Laperche C, Buces E, Aguilera-Morillo MC, Picornell A, González-Rivera M, Lillo R, Santos N, Martín-Antonio B, Guillem V, Nieto JB, González M, de la Cámara R, Brunet S, Jiménez-Velasco A, Espigado I, Vallejo C, Sampol A, Bellón JM, Serrano D, Kwon M, Gayoso J, Balsalobre P, Urbano-Izpizua Á, Solano C, Gallardo D, Díez-Martín JL, Romo J, Buño I
A novel predictive approach for GVHD after allogeneic SCT based on clinical variables and cytokine gene polymorphisms.
Blood Adv24 Jul 2018, 2(14)1719-1737.
Despite considerable advances in our understanding of the pathophysiology of graft-versus-host disease (GVHD), its prediction remains unresolved and depends mainly on clinical data. The aim of this study is to build a predictive model based on clinical variables and cytokine gene polymorphism for predicting acute GVHD (aGVHD) and chronic GVHD (cGVHD) from the analysis of a large cohort of HLA-identical sibling donor allogeneic stem cell transplant (allo-SCT) patients. A total of 25 SNPs in 12 cytokine genes were evaluated in 509 patients. Data were analyzed using a linear regression model and the least absolute shrinkage and selection operator (LASSO). The statistical model was constructed by randomly selecting 85% of cases (training set), and the predictive ability was confirmed based on the remaining 15% of cases (test set). Models including clinical and genetic variables (CG-M) predicted severe aGVHD significantly better than models including only clinical variables (C-M) or only genetic variables (G-M). For grades 3-4 aGVHD, the correct classification rates (CCR1) were: 100% for CG-M, 88% for G-M, and 50% for C-M. On the other hand, CG-M and G-M predicted extensive cGVHD better than C-M (CCR1: 80% vs. 66.7%, respectively). A risk score was calculated based on LASSO multivariate analyses. It was able to correctly stratify patients who developed grades 3-4 aGVHD (
McCurdy SR, Zhang MJ, St Martin A, Al Malki MM, Bashey A, Gaballa S, Keesler DA, Hamadani M, Norkin M, Perales MA, Reshef R, Rocha V, Romee R, Solh M, Urbano-Ispizua A, Waller EK, Fuchs EJ, Eapen M
Effect of donor characteristics on haploidentical transplantation with posttransplantation cyclophosphamide.
Blood Adv13 Feb 2018, 2(3)299-307.
We studied the association between non-HLA donor characteristics (age, sex, donor-recipient relationship, blood group [ABO] match, and cytomegalovirus [CMV] serostatus) and transplant outcomes after T-cell-replete HLA-haploidentical transplantation using posttransplantation cyclophosphamide (PT-Cy) in 928 adults with hematologic malignancy transplanted between 2008 and 2015. Siblings (n = 358) and offspring (n = 450) were the predominant donors, with only 120 patients having received grafts from parents. Although mortality risks were higher with donors aged 30 years or older (hazard ratio, 1.39;
Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited
Martín-Antonio B, Suñe G, Perez-Amill L, Castella M, Urbano-Ispizua A
Natural Killer Cells: Angels and Devils for Immunotherapy.
Int J Mol Sci29 Aug 2017, 18(9) . Epub 29 Aug 2017
In recent years, the relevance of the immune system to fight cancer has led to the development of immunotherapy, including the adoptive cell transfer of immune cells, such as natural killer (NK) cells and chimeric antigen receptors (CAR)-modified T cells. The discovery of donor NK cells' anti-tumor activity in acute myeloid leukemia patients receiving allogeneic stem cell transplantation (allo-SCT) was the trigger to conduct many clinical trials infusing NK cells. Surprisingly, many of these studies did not obtain optimal results, suggesting that many different NK cell parameters combined with the best clinical protocol need to be optimized. Various parameters including the high array of activating receptors that NK cells have, the source of NK cells selected to treat patients, different cytotoxic mechanisms that NK cells activate depending on the target cell and tumor cell survival mechanisms need to be considered before choosing the best immunotherapeutic strategy using NK cells. In this review, we will discuss these parameters to help improve current strategies using NK cells in cancer therapy. Moreover, the chimeric antigen receptor (CAR) modification, which has revolutionized the concept of immunotherapy, will be discussed in the context of NK cells. Lastly, the dark side of NK cells and their involvement in inflammation will also be discussed.