scholarly journals Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy

2021 ◽  
Vol 9 (5) ◽  
pp. e001743
Author(s):  
Abraham Nissani ◽  
Shaked Lev-Ari ◽  
Tomer Meirson ◽  
Elad Jacoby ◽  
Nethanel Asher ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Clinical Response ◽  
Serum Levels ◽  
Bone Marrow Suppression ◽  
Maximum Effect ◽  
Operating Characteristics ◽  
Lymphocyte Ratio

BackgroundAdoptive cell therapy with T cells genetically engineered to express a chimeric antigen receptor (CAR-T) or tumor-infiltrating T lymphocytes (TIL) demonstrates impressive clinical results in patients with cancer. Lymphodepleting preconditioning prior to cell infusion is an integral part of all adoptive T cell therapies. However, to date, there is no standardization and no data comparing different non-myeloablative (NMA) regimens.MethodsIn this study, we compared NMA therapies with different doses of cyclophosphamide or total body irradiation (TBI) in combination with fludarabine and evaluated bone marrow suppression and recovery, cytokine serum levels, clinical response and adverse events.ResultsWe demonstrate that a cumulative dose of 120 mg/kg cyclophosphamide and 125 mg/m2 fludarabine (120Cy/125Flu) and 60Cy/125Flu preconditioning were equally efficient in achieving deep lymphopenia and neutropenia in patients with metastatic melanoma, whereas absolute lymphocyte counts (ALCs) and absolute neutrophil counts were significantly higher following 200 cGyTBI/75Flu-induced NMA. Thrombocytopenia was most profound in 120Cy/125Flu patients. 30Cy/75Flu-induced preconditioning in patients with acute lymphoblastic leukemia resulted in a minor ALC decrease, had no impact on platelet counts and did not yield deep neutropenia. Following cell infusion, 120Cy/125Flu patients with objective tumor response had significantly higher ALC and significant lower inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). Receiver-operating characteristics curve analysis 7 days after cell infusion was performed to determine the cut-offs, which distinguish between responding and non-responding patients in the 120Cy/125Flu cohort. NLR≤1.79 and PLR≤32.7 were associated with clinical response and overall survival. Cytokine serum levels did not associate with clinical response in patients with TIL. Patients in the 120Cy/125Flu cohort developed significantly more acute NMA-related adverse events, including thrombocytopenia, febrile neutropenia and cardiotoxicity, and stayed significantly longer in hospital compared with the 60Cy/125Flu and TBI/75Flu cohorts.ConclusionsBone marrow depletion and recovery were equally affected by 120Cy/125Flu and 60Cy/125Flu preconditioning; however, toxicity and consequently duration of hospitalization were significantly lower in the 60Cy/125Flu cohort. Patients in the 30Cy/75Flu and TBI/75Flu groups rarely developed NMA-induced adverse events; however, both regimens were not efficient in achieving deep bone marrow suppression. Among the regimens, 60Cy/125Flu preconditioning seems to achieve maximum effect with minimum toxicity.

scholarly journals Anti-CD19 Chimeric Antigen Receptor T Cell Treatment of Relapsed /Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant to Bruton's Tyrosine Kinase (BTK) Inhibitor

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Weihong Chen ◽  
Xin Du ◽  
Wenyujing Zhou ◽  
Changru Luo ◽  
Xiaoqing LI
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymph Nodes ◽  
Peripheral Blood ◽  
Serum Levels ◽  
Car T Cell ◽  
Car T ◽  
Btk Inhibitor

CASE PRESENTATION: A 68-year-old male was diagnosed with CLL/SLL in November 2007. Bone marrow asp/bx: 36.5% lymphocytes, 78% CD19, 65% ATM (11q22 deleted) positive cells, 13.5% D13S25 (13q14.3 deleted). On December 10, 2009, the patient took FCR scheme for five cycles, followed by FR scheme for one cycle, and then a month of Chlorambucil. On September 5, 2013, the patient took BR scheme for four cycles with no effect. From March 2015 to Feb 2016, 420 mg of Ibrutinib was administered daily. On January 15, 2016, the patient developed swollen lymph nodes in his right neck with intermittent lumps, fever and nausea. He was admitted into the hospital at Feb 2, 2016. Test results: multiple swollen superficial lymph nodes over the body, with the biggest measuring 60×30mm on the right neck, with no tenderness. Supplementary tests: peripheral white blood cells (WBC) 11.94×10E9/L, lymphocyte 7.5×10E9/L, CD19 cells 6.73×10E9/L, bone marrow lymphocyte 62%, peripheral blood lymphocyte 52%. Immunophenotype: CD5, CD19, CD20dim, CD23, CD11b dim, HLA-DR expression, visible CD5+CD19+ cell clusters, and visible immunoglobulin cKappa with restricted expression. On March 10, 2016, peripheral blood platelet 60 × 10E9/L, CD19 cells 1.94×10E9/L, lactate dehydrogenase 460U/L, FER 115.6ng/ml, hepatitis B virus carrier. Diagnosis: CLL/SLL IV stage, ATM (11q22) deletion, D13S25 (13q14. 3) positive, CD19 positive. Relapse of CLL/SLL occurred again after four months and at this stage the patient was considered for therapy in a clinical trial of CD19-specific chimeric antigen receptor (CAR-) T cell therapy. Ethical approval and informed consent were obtained for anti-CD19 CAR T Cell treatment of ibrutinib resistance in relapsed/refractory CLL/SLL. We infused autologous T cells transduced with a CAR T 19 retroviral vector with CLL/SLL at doses of 3.3 × 10E8 CART19 cells on Mar. 16 2016. Patients were monitored for responses, toxic effects, and the expansion and persistence of circulating CART19 cells. After CART19 cells were infused, the patient experienced chills, fever, headache, weak, anorexia, nausea, shortness of breath, chest tightness, heart palpitation, hypotension and shock for 9 days. The serum levels of IFN-Υ were at their highest at day 7 after CAR T cells infusion. Serum interleukin 6 (IL-6) was at 680pg/ml and CD3+ cells were 97.5%, CD8+ cells 72.8% (18.7-32.8%), FER was 1529.5ng/ml (Normal No. 22-322ng/ml) 14 days after CAR-T cell infusion. The serum levels of IL-6 were at their highest at day14. The patient was diagnosed as having cytokine release syndrome. After the patient took the anti-IL-6R antibody and anti-TNF antibody, he began to recover gradually. Enlarge lymph nodes shrunk after being infused with CART19 cells for 7 days. The peripheral blood CD19 B lymphocytes were 0 on day 14 after infused with CAR T19 cells. Q-PCR was used to detect the amount of the peripheral blood CART19 cells, which stood at 5485 copies/μl, 924 copies/μl, 191 copies/μl respectively 2 weeks, 6 weeks and 3 months after infusing with CART19 cells. The peripheral blood CART 19 cells were not detectable 4 months after infusing with CART19 cells until present. The lymphadenopathy was decreased gradually after 14 days of infusion. The MRI test showed that lymphadenopathy reduced markedly or disappeared after 6 months of infusion. ATM (11q22 deleted) negative, D13S25 (13q14.3 deleted) negative. After treatment with CAR T 19 cell therapy for 53 months, the patient remained disease-free, the patient's lymph nodes, lymphocytes and I mmunoglobulins were normal. CONCLUSIONS : Cancer immunotherapy as a method of cancer treatment is the most effective after conventional treatments such as radiotherapy, chemotherapy, and surgery. For BTK Inhibitor resistance in relapsed and refractory CD19+ CLL/SLL, CD19 is a favorable target, because the expression of CD19 is limited to B cells and not present in other tissues or cells. Currently, the efficacy of this treatment in treating CLL/SLL remains to be seen. The effects of chemotherapy on the patient's B cell lymphoma are negligible, due to the fact that his CLL/SLL have become relapsed and refractory. As a result we chose the CAR T19 cell therapy genetic engineering technique as a method of treatment, to which the patient has responded well. Therefor, CAR T cell technology overcome the limitations of existing cancer therapies and has great potential for development and application. Disclosures No relevant conflicts of interest to declare.

scholarly journals Impact of pre‐therapy glioblastoma multiforme microenvironment on clinical response to autologous CMV‐specific T‐cell therapy

2019 ◽  
Vol 8 (11) ◽  
Author(s):  
David G Walker ◽  
Reshma Shakya ◽  
Beth Morrison ◽  
Michelle A Neller ◽  
Katherine K Matthews ◽  
...  
Keyword(s):  
T Cell ◽  
Glioblastoma Multiforme ◽  
Cell Therapy ◽  
Clinical Response ◽  
T Cell Therapy

Neurological adverse events following CAR T-cell therapy: a real-world analysis

Immunotherapy ◽  
2020 ◽  
Vol 12 (14) ◽  
pp. 1077-1082
Author(s):  
Ajeet Gajra ◽  
Marjorie E Zettler ◽  
Eli G Phillips Jr ◽  
Andrew J Klink ◽  
Jonathan K Kish ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Real World ◽  
Antigen Receptor ◽  
B Cell Lymphomas ◽  
T Cell Therapy ◽  
Large B Cell

Aim: To characterize real-world neurological adverse events (AEs) associated with chimeric antigen receptor T-cell therapies in patients with refractory/relapsed large B-cell lymphomas. Materials & methods: Postmarketing case reports from the US FDA AEs reporting system involving axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) for large B-cell lymphomas were analyzed. Results: Of 804 AE cases identified (637 axi-cel, 167 tisa-cel), 428 (67%) of axi-cel cases and 43 (26%) of tisa-cel cases reported neurological AEs. Compared with cases without neurological AEs, significant associations were observed between neurological AEs and use of axi-cel, age ≥65 years, and the outcome of hospitalization. Conclusion: Neurological AEs were common with chimeric antigen receptor T-cell therapy in the real world and largely reflected those reported in clinical trials.

Activity Of Single Agent Temsirolimus and Associated Impact On Bone Marrow Vascularization and T-Cell Composition In Patients With Myelodysplastic Syndromes – Result Of The Prospective Temds Trial Of The German MDS-SG

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2808-2808
Author(s):  
Martin Wermke ◽  
Claudia Schuster ◽  
Claudia Schönefeldt ◽  
Christiane Jakob ◽  
Malte von Bonin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Adverse Events ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Single Agent ◽  
Infectious Complications ◽  
T Cell Subsets ◽  
Concentration Data ◽  
Cell Composition

Abstract Introduction Enhanced progenitor proliferation, bone marrow (BM) hypervascularization and disturbed immune regulation contribute to the pathogenesis of myelodysplastic syndromes (MDS). Inhibition of mammalian-target of rapamycin (mTor) by temsirolimus (TEM) might be a promising strategy to target these disease-specific cellular alterations. We report on the effects of single agent TEM on the clinical course as well as on immune composition and BM vascularization of MDS patients treated within the prospective, multicenter “TEMDS”-trial (NCT01111448). Patients, Materials and Methods Twenty patients being either IPSS low/int-1 MDS (n = 9) or IPSS int-2/high after azacitidine failure were treated with TEM at a dose of 25 mg/week in the absence of toxicity or disease progression. BM was reevaluated after 4 months of treatment with the option of TEM continuation for a maximum of 12 months in responding patients. Translational research within this study included flowcytometry-based measurement of changes in T-cell composition as well as determination of cytokine levels and BM-vascularization prior to and after TEM. Results Of 20 patients treated, 15 discontinued TEM treatment prematurely due to intolerable side effects (n = 11), infectious complications (n = 3), or progression to AML (n = 1). Fatigue, stomatitis and profound leukopenia were the most frequent adverse events. A total of 13 severe adverse events were encountered in 10 patients and 1 patient died of infectious complications during TEM treatment. Of the 5 patients who were treated for at least 4 months and underwent regular BM reevaluation, none showed signs of response according to IWG criteria. TEM treatment resulted in a remarkable, although non-significant, decrease in total number of lymphocytes in the pB (pre: 74.6%, post: 48.4%, p = 0,083) and BM (pre: 23.5% post: 20.1%, p = 0.123). Within the T-helper cell compartment a trend towards an increase in regulatory T-cell (Treg) frequency was observed (pB: pre: 6.0 %, post: 6.4 %, p = 0.083). Moreover, the balance between naive (CD45RA+/CD45RO-) and activated/memory (CD45RA-/CD45RO+) Treg shifted significantly in favor of the latter (p = 0.004). Plasma analysis in BM and pB revealed, that these changes were obviously not mediated by alterations in TGFβ plasma levels. In a total of 12 assessable patients, a significant (p = 0.006) decrease of BM vascularization was observed after treatment with TEM for a median of 5 weeks (Fig. 1). There were, however, no changes in the medullary or peripheral blood VEGF concentration (data not shown). Conclusions Selective inhibition of the mTOR signaling cascade in MDS patients results in specific alterations of the composition of T-cell subsets as well as BM vascularization. Given the absence of any hematological response we suggest that these drug-induced modifications cannot alter the natural course of the disease. Disclosures: Wermke: Pfizer: Research Funding. Off Label Use: Temsirolimus is licensend for the treatment of MCL and RCC but not MDS. Platzbecker:Pfizer: Research Funding.

Adoptive T-cell therapy combined with intra-lesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20022-e20022
Author(s):  
Amir Khammari ◽  
Jean-Marc Limacher ◽  
Jean-Michel NGuyen ◽  
Melanie Saint-Jean ◽  
Gaelle Quereux ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Cell Therapy ◽  
Translational Research ◽  
Stable Disease ◽  
Objective Response ◽  
Interferon Γ ◽  
Adoptive T Cell Therapy ◽  
Surgical Biopsy ◽  
T Cell Therapy

e20022 Background: The purpose of this study was to evaluate the feasibility, safety and efficacy of adding intra-tumoral injections of TG1042 (Adenovirus 5 expressing Interferon-γ) to adoptive T cell therapy in patients with advanced stage melanoma. Methods: This was a monocentric phase I/II study. The main inclusion criteria were: stage IIIc/IV melanoma, age 18 to 75, at least one injectable metastasis. Tumor infiltrating lymphocytes (TILs) produced from a surgical biopsy of a lesion were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x1010 viral particles per lesion (in up to 6 lesions) every 2 weeks from day -15 to month 2 and then every month up to month 11 or progression. Primary objective was the safety of the procedure; secondary objectives included response according to RECIST and translational research. Results: Eighteen patients have been included. The TILs production was successful in 16 of them. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections were the most frequent adverse events observed. No grade 3 or 4 treatment related adverse events was recorded. Among the 13 patients evaluable for tumor response 4 patients (31%) had an overall objective response (2 complete, 2 partial), 1patient had a stable disease and 8 progressed. When considering only the injected lesions 6 (46%) had an objective response (3 complete, 3 partial), 3 had a stable disease and 4 progressed. Distant responses in non-injected lesions were observed for 2 patients. Translational research on cutaneous biopsies before and after injections (3 months) showed an increase of CD8 T lymphocytes, IFN-γ and STAT 1 expression in 3 patients. Conclusions: This study demonstrates that co-delivery of TILs and intra lesional TG1042 is feasible and safe. Stimulation of innate immunity by adenovirus expressing interferon-γ could contribute to reverse the immunotolerant profile of the tumour environment. These results support to further explore combined immunotherapies in the treatment of melanoma. Clinical trial information: NCT01082887.

scholarly journals Combination Therapy of Allogeneic HSCT and In Vivo Activated iNKT Cells Prevents Acute Gvhd While Augmenting GVL Effect

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4439-4439
Author(s):  
Samuel Zeng ◽  
Qingxiao Song ◽  
Shanshan Tang ◽  
Xi Wang ◽  
Yuchen Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Combination Therapy ◽  
Cell Therapy ◽  
Natural Killer ◽  
Acute Gvhd ◽  
Inkt Cell ◽  
Inkt Cells ◽  
Allogeneic Hsct

Adult acute lymphoblastic leukemia (ALL) is a highly aggressive cancer with poor clinical prognosis and high relapse rate. Whereas allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for highly differentiated hematologic malignancies, allo-HSCT provides only limited benefits for treating ALL with relapses frequent. Additionally, the development of graft-versus-host-disease (GVHD) remains a major concern for allo-HSCT recipients. Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that express both a semi-invariant T cell receptor and natural killer cell markers. They recognize lipid antigens presented by non-polymorphic CD1d and have been reported to directly target CD1d+ solid tumors. Many B-ALL, including the P210 B-ALL cell line, are also CD1d+. Clinically, increased iNKT cells have simultaneously been correlated with reduced risk of developing acute GVHD and lower rates of malignant relapse. Because iNKT cells comprise only a tiny fraction of total T cells, we established a protocol to insert an iNKT TCR into murine HSC, thereby generating retrogenic mice with 5-10x expansion of iNKT cells in spleen and liver. Although engineered T cell therapy, including CD19-CART therapy, has proven to be effective in inducing remission in many B-ALL patients, when used as a monotherapy, relapse remains a major obstacle. We therefore tested whether a combination of allo-HSCT and iNKT cell therapy could robustly prevent GVHD while preserving graft-versus-leukemia effects (GVL). To test whether the addition of iNKT cells into allo-graft was capable of preventing acute GVHD (aGVHD), lethally irradiated BALB/C were given B6 bone marrow (2.5 x 106) and whole splenocytes (2.5 x 106, 5 x 106, or 10 x 106) from either B6 or retrogenic B6-iNKT mice. Mice that received 5 x 106 B6 splenocytes developed lethal aGVHD and became moribund by Day 10. Half of the mice that received 2.5 x 106 B6 splenocytes develop lethal aGVHD and died by Day 20. In contrast, only half of the mice that received 5 x 106 or 10 x 106 B6-iNKT splenocytes developed lethal aGVHD by Day 20, and all recipients of 2.5 x 106 B6 splenocytes remained alive by Day 20, suggesting the addition of iNKT cells into allograft may reduce the severity of aGVHD. To test whether adding iNKT cells to allograft could enhance GVL without causing GVHD, BALB/C mice with pre-established P210 B-ALL leukemia were given allo-HSCT with or without iNKT cell addition. Initially, our data showed freshly isolated iNKT cells were rapidly cleared following transplantation. We therefore included lethally irradiated P210 loaded with α-Galactosylceramide (α-Galcer) as adjuvant, and were able to see robust expansion of iNKT cells in vitro and in vivo (>20% vs <1% in WT in BM and Liver). Additionally, we found that HSCT recipients that also received iNKT cells were able to fully clear bone marrow residing B-ALL cells by Day8, compared to less than half in control, suggesting an important role of iNKT cells for targeting bone marrow residing B-ALL cells to prevent relapse. Taken together, combination therapy of allogeneic HSCT with infusion of donor-type iNKT cells activated via irradiated α-Galcer-loaded host-type ALL represent a novel approach for preventing GVHD and augmenting GVL effect against ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Incidence and Causes of Prolonged Hematologic Toxicity after Chimeric Antigen Receptor T Cell Therapy: A City of Hope (COH) Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 40-41
Author(s):  
Geoffrey Shouse ◽  
Thai Cao ◽  
Jianying Zhang ◽  
Matthew Mei ◽  
Alex F. Herrera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Hematologic Toxicity ◽  
T Cell Therapy ◽  
Car T ◽  
Grade 3

Introduction The most common toxicities after chimeric antigen receptor (CAR) T cell therapy include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and hematologic toxicity. The reported grade 3 and higher neutropenia, anemia and thrombocytopenia lasting longer than 30 days occurred in 15%, 3% and 18% of patients treated with Axicabtagene ciloleucel (Axi-Cel) (Yescarta package insert). Early hematologic toxicity after lymphodepleting chemotherapy (LDP) prior to infusion of CAR T cells is expected. However, prolonged cytopenias lasting longer than 28 days cannot be explained by the toxicity of LDP alone. Here, we described the incidence and potential causes for prolonged cytopenias in patients (pts) treated with Axi-cel for r/r aggressive B cell lymphoma. Methods We retrospectively analyzed 78 consecutive pts receiving Axi-cel at our institution between November 1, 2017 and April 1, 2020. This study was conducted with approval from the COH Institutional Review Board. All patients received standard LDP regimen with cyclophosphamide and fludarabine followed by infusion of Axi-cel at day 0. Clinical response was determined between day 28-35. Neutropenia, anemia and thrombocytopenia were defined as meeting the NCI CTCAE v5.0 criteria and were considered prolonged if lasting &gt;28 days. CRS and ICANS severity were graded using the ASTCT criteria. Results A total of 78 pts were included with the median age of 61 years (range, 22-77), 33% &gt; 65 years old, 68% male. Seventeen (22%) pts had transformed follicular lymphoma (tFL), 55 had diffuse large (DLBCL), and 6 (8%) had primary mediastinal (PMBCL). Median lines of prior treatment were 3 (range 2-6) with 18 (23%) having prior autologous stem cell transplant (ASCT). Responses were seen in 71 pts (91%), with 25 (32%) partial responses (PR) and 46 (59%) complete responses (CR) at the first assessment. Forty-eight pts (62%) remained progression free with a median follow up of 252 days (range, 56-785). CRS was noted in 67 pts (86%), with 6 (8%) grade 3 (G3), while 35 (45%) developed ICANS, with 8 (10%) G3. No grade 4 or higher CRS or ICANS were seen. All pts developed ≥ G3 neutropenia and lymphopenia that lasted a median of 51 days (range 7-456), and 39 days (range 6-737) respectively. G3 and higher anemia and/or thrombocytopenia were seen in 49% of pts. Prolonged ≥ G3 cytopenias were seen in 72% of pts with 47%, 23%, and 29% showing prolonged neutropenia, anemia and thrombocytopenia respectively. Importantly, CRS was associated with a statistically significant increase (79% vs 27%) in risk of developing prolonged cytopenias (p=0.001). In addition, a biphasic pattern of hematologic toxicity in which late cytopenias recurred after a period of recovery, was noted in 8% of pts. These delayed cytopenias were associated with lymphocyte recovery after CAR T cell administration. Finally, 7% of pts with prolonged ≥ G3 cytopenias developed therapy related MDS: the median age in this group was 60 (range 50-74), with a median of 3 prior lines of therapy (range 2-4), and 75% having prior ASCT. Overall, infections were seen in 14 pts (18%) and 9 were after day 28. In pts with prolonged ≥ G3 neutropenia, rates of infection beyond day 28 (9%) were similar to those without prolonged neutropenia (8%). Use of GCSF did not correlate with increased CRS, ICANS or prolonged cytopenias. Conclusion Our real-world experience reported high response rates and favorable incidences of CRS, and ICANS with no grade 4 noted in comparison to that described in clinical trials and by others. We identified CRS as a significant risk factor associated with development of prolonged hematologic toxicity and this may indicate an underlying bone marrow suppressive effect of the inflammation associated with CRS. Like others, we also observed a biphasic hematologic toxicity associated with recovery from B cell aplasia. Due to significant rates of therapy related MDS, bone marrow evaluation before and after CAR T therapy should be considered, especially in patients with prior transplant. Last, despite the high rates of prolonged hematologic toxicity, infection rates were not higher in patients with prolonged neutropenia, underscoring the importance of supportive medical management. Disclosures Shouse: Kite Pharma: Honoraria, Speakers Bureau. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Herrera:AstraZeneca: Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Karyopharm: Consultancy. Zain:Seattle Genetics: Research Funding; Mundi Pharma: Research Funding; Kyowa Kirin: Research Funding. Siddiqi:BeiGene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Speakers Bureau; TG Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Speakers Bureau; Oncternal: Research Funding; AstraZeneca: Consultancy, Research Funding, Speakers Bureau. Popplewell:Pfizer: Research Funding; Novartis: Research Funding; Roche: Research Funding. Budde:Amgen: Research Funding; Merck: Research Funding; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding; Roche: Consultancy; Gilead Sciences: Consultancy; Kite, a Gilead Company: Consultancy.

scholarly journals Allogeneic CAR-T Cell Therapy for Treatment of Relapse after Allo-HSCT in Patients with Refractory CML Lymphoid Blast Crisis: Significance of HLA Matched Donor/Patient Pair in the Safety/Efficacy of CAR-T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4275-4275 ◽  
Author(s):  
Kai Sun ◽  
Xuejun Zhang ◽  
Zhen Wang ◽  
Yuqing Chen ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Blast Crisis ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: CD19-specific CAR-T cells have shown promise in the treatment of relapsed or refractory Ph+ ALL. It remains to be established whether allogeneic CAR-T cells have clinical activity in patients with relapsed CML lymphoid blast crisis with a history of allo-HSCT. Here we report our experience in two cases of allogeneic CAR-T cell therapy for treatment of relapse after allo-HSCT in patients with refractory CML lymphoid blast crisis. Methods: For manufacture of allogeneic CAR-T cells, peripheral blood mononuclear cells were collected from the same stem cell donor. Lentiviral construction and generation of CAR-T cells, clinical protocol design, assessment and management of cytokine release syndrome (CRS), were performed as described in our previous report (Leukemia. 2017;31:2587-2593). Fludarabine and cyclophosphamide had been administered for lymphocyte depletion before allogeneic CAR-T cells infusion. Patients: Patient 1 was a 52-year-old woman with refractory CML lymphoid blast crisis, who had a relapse after undergoing allo-HSCT from her daughter (HLA-10/10). Her initial examinations of peripheral blood and bone marrow were consistent with the diagnosis of CML lymphoid blast crisis. Cytogenetics and molecular analysis confirmed the presence of t(9;22)(q34;q11) and BCR-ABL1 210 fusion protein. In February 2017, examination of bone marrow revealed a further increase of lymphoblasts to 83.2%. In addition, ABL1 kinase mutations (Y253H and E255K/V) were identified. The patient underwent HLA 10/10-matched allo-HSCT without acute GVHD. A remission with a negative test for BCR-ABL1 210 and 99.62% donor chimerism had been achieved, then she had a lymphoblastic relapse occurred 2 months after allo-HSCT. Consistently, BCR-ABL1 210 turned positive, and chimerism analysis showed 67.4% donor chimerism. 3 weeks after relapse, allogeneic CAR-T cells were infused at the dose of 5×106 /kg CD19-specific CAR-T cells. Patient 2 was a 39-year-old male patient with relapsed CML lymphoid blast crisis with a history of allo-HSCT. He had received a diagnosis of CML chronic phase 7 years earlier. Bone marrow revealed a karyotype of 46, XY, t(3;9;22)(q27;q34;q11) and BCR-ABL mRNA transcript. From April 2011 to September 2012, the patient was treated with nilotinib. In September 2012, bone marrow examination revealed 78% lymphoblasts, thus the diagnosis of CML lymphoid blast crisis was established. In December 2012, the patient underwent HLA 7/10-matched sibling allo-HSCT (from his brother) without evidence of GVHD and maintained CR for 2 years. In December 2014, the patient developed bone marrow relapse (lymphoblast 9.5%) and extramedullary leukemia (testicular involvement) harboring the BCR-ABL-T315I mutation. During 2014 to 2018, the patient received multiple courses of CIKs, HDMTX and DLI, but failed to achieve CR. In March 2018, the patient received healthy donor derived allogeneic CAR19 T cells (2×105/kg) therapy. Result: Before CAR-T cells infusion, both patients with refractory CML lymphoid blast crisis had a relapse after successful allo-HSCT. Approximately 1 month after CAR-T cells infusion, a persistent morphologic remission, a recovering BM, and complete absence of BCR-ABL mRNA transcripts confirmed morphologic and molecular remission in both patients. Consistent with this, flow cytometry could not detect blasts or CD19+ B lineage cells. Patient 1 did not experience toxicities and allogeneic CAR-T cell therapy was well tolerated. Patient 2 developed severe CRS (Gr 4) including high-grade fevers (>40°C), hypotension, hypoxia, mental status changes, and seizures. These episodes ran for approximately 1 week before they were halted by treatment with steroids plus tocilizumab, and plasma exchange. The toxicity of allogeneic CAR-T cells is correlated with high levels of IL-6, IFN-γ, TNF-a, and CRP. Conclusion: The clinical outcomes from these 2 patients demonstrate the in vivo efficacy of allogeneic CD19-targeted T cells to induce clinical, morphology and molecular remissions as well as B cell aplasia in adults with relapsed CML lymphoid blast crisis with a history of allo-HSCT. The efficacy of allogeneic CAR-T cell therapy may not always be related to the risk of severe CRS. The degree of HLA matching may have a major impact on the prevention of CRS after allogeneic CAR-T cell therapy. Fully HLA-matched-pair may increase the safety and efficacy of the allogeneic CAR-T cell therapy. Disclosures No relevant conflicts of interest to declare.

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