Introduction
Mantle cell lymphoma (MCL) is a distinct histological type of B cell lymphoma with a median age of 65–68 years old at diagnosis [
1]. MCL has a predominantly aggressive clinical course and poor prognosis, with a median survival of 3–5 years, due to the incurability of disease with conventional chemotherapy [
2,
3]. A highly unmet need for effective treatments for patients with relapsed or refractory (r/r) MCL remains. Recently discovered agents, such as proteasome inhibitors, immunomodulatory drugs, and inhibitors of B cell lymphoma-2 (BCL-2) and Bruton’s tyrosine kinase (BTK), have shown efficacy for r/r MCL, but the responses are generally not durable beyond 2 years [
4–
7].
Chimeric antigen receptor (CAR) T-cell therapy has emerged as a novel treatment modality for r/r non-Hodgkin’s lymphoma (NHL). Either CD28- or 4-1BB-based CAR T cells can improve the outcomes of patients with r/r diffuse large B-cell lymphoma, thereby resulting in durable remissions in approximately 40% of heavily pretreated patients [
8,
9]. However, the long-term results of CAR T cells in MCL are not defined well [
10–
12]. In our clinical trial, an enrolled 70-year-old patient with r/r MCL achieved sustainable remission lasting 48 months after CAR T-cell therapy (at the time of submission of this manuscript). CAR T-cell-related toxicities were also mild and tolerated well even in this elderly patient.
Study design of phase I/II clinical trial of anti-CD19 CAR T-cell therapy for r/r B-cell neoplasms
The trial (ClinicalTrials.gov number: NCT02537977) was designed for the assessment of the safety and feasibility of infusing autologous CAR T cells in patients with r/r B-cell neoplasms at Tongji Hospital of Tongji University School of Medicine. The CAR used in this work included a murine anti-CD19 single-chain variable fragment, a 4-1BB costimulatory domain, and a CD3
z T-cell activation domain. Peripheral blood mononuclear cells collected from patients were used in the preparation of CAR T cells. Cell culture and lentiviral transductions were performed in an almost identical manner as described previously [
13]. The patients received lymphodepleting chemotherapy with FC regimen (25 mg/m
2 fludarabine and 300 mg/m
2 cyclophosphamide daily for 3 days) on days –4, –3, and –2 before CAR T-cell infusion. At 2 days after chemotherapy, the patient received 1×10
6 autologous CAR-positive T cells/kg that was split into 3 consecutive daily intravenous infusions (10% on day 0, 30% on day 1, and 60% on day 2; Fig. S1A).
Anti-CD19 CAR T cells induced durable response lasting 48 months in elderly patient with r/r MCL
The 70-year-old male patient with a 20-year history of diabetes was initially diagnosed with Ann-Arbor Stage IVA MCL in November 2012. The patient showed no response to initial treatment with two cycles of R-CHOP (rituximab, prednisone, vincristine, doxorubicin, and cyclophosphamide). Then, the patient received four cycles of FCR (fludarabine, cyclophosphamide, and rituximab), thereby achieving a partial remission. At 1 month after the 4th cycle of the FCR regimen, the patient developed fulminant hepatitis caused by hepatitis B virus reactivation, which required hospitalization. Afterward, the patient received no further chemotherapy until progressive disease was noted in February 2015. Then, the patient was treated with modified R-hyperCVAD (rituximab, vincristine, adriamycin, cyclophosphamide, and dexamethasone). As the patient developed sepsis caused by Escherichia coli during the chemotherapy, the subsequent therapy was discontinued.
In July 2015, the patient was enrolled in the clinical trial of the anti-CD19 CAR T cells at Tongji Hospital of Tongji University School of Medicine. At the time of evaluation for the trial, serial computed tomography (CT) scans showed that the patient had progressive lymphoma that involved bilateral inguinal and para-aortic lymph nodes with splenomegaly. Bone marrow evaluation showed a 24% infiltration by MCL lymphocytes, and fluorescence
in situ hybridization (FISH) analysis confirmed the presence of the translocation t(
11;
14)(q11, q32). Renal function tests showed a low glomerular filtration rate (GFR, 31.68 mL/min/1.73 m
2), and ECG showed ventricular premature beats. The patient experienced the rapid regression of the enlarged inguinal lymph nodes and spleen on physical examination by day 21 after CAR T-cell infusions. CT scan that was performed on day 35 revealed the partial resolution of the adenopathy (Fig. 1). The response continued, and the patient achieved the complete remission of lymphoma documented by the CT scan and medullary remission by the bone marrow biopsy 3 months after CAR T-cell infusions (Fig. 1A and 1B). FDG-PET that was performed 6 months after CAR T-cell infusions further confirmed the complete metabolic remission of lymphoma (Fig. 1C). Afterward, the patient started a 6-month follow-up. On the last evaluation, after a follow-up period of 48 months, the patient was still well and in complete remission.
Robust expansion and long-term persistence of anti-CD19 CAR T cells in blood of patient with MCL
Flow cytometry and quantitative polymerase chain reaction (qPCR) showed that CAR T cells in blood expanded robustly by day 21 after CAR T-cell infusions (Fig. 2A and 2B). At peak levels, CAR T cells in blood accounted for more than 60% of the circulating lymphocytes from day 15 through day 18. The blood CD19+ B cells were not detected from day 15, which coincided with the expansion of the anti-CD19 CAR T cells in blood (Fig. 2A). CAR T cells also remained detectable by flow cytometry (0.065% of blood T cells, Fig. 2C), and CD19+ B cells remained absent on the last evaluation for the 48-month follow-up (Fig. 2C).
CAR-T cell-related toxicities were mild and tolerated well in patient with MCL
The patient experienced immediate grade 2 chills and fever accompanied by transient moderate respiratory distress occurring within 2 h after infusion on days 0 and 1, respectively. The symptoms were resolved with acetaminophen administration and oxygen therapy. Subsequently, the patient had a recurrent fever (maximum temperature, 39.3 °C) from day 11 through day 15. Grade 1 cytokine release syndrome (CRS) was diagnosed based on the concurrently increased C-reactive protein and serum cytokine levels (Fig. S1B and S1C). Subsequently, lactic dehydrogenase levels and uric acid values increased from day 12 through day 18, which was consistent with laboratory tumor lysis syndrome. These biochemical changes were reversible in a week without additional intervention. On day 19, the patient developed a respiratory tract infection with a moderate fever and cough, which was resolved with antibiotic treatment. Other acute side effects that may be related to the study treatment included grade 1 hypokalemia beginning from day 15 through day 30. Although the patient had grade 2 decrease in GFR at the baseline, it did not deteriorate and improved to grade 1 from day 27 through to the most recent follow-up.
The concentrations of the serum immunoglobulins (Igs), including IgG, IgA, and IgM, decreased significantly by 74%, 87%, and 95% during the first 3 months after CAR-T-cell infusions, respectively, and have stayed at these low levels ever since (Fig. S2). The patient received intravenous 0.3 mg/kg immune globulin replacement every 2–3 months from 6 months after CAR-T-cell infusions. During the 48-month follow-up, the patient did not have susceptibility to infection or increase in the incidence of other diseases.
Conclusions and discussion
Treatment with r/r MCL generally represents a difficult clinical challenge. The patients who are ineligible for intensive chemotherapy and hematopoietic stem cell transplantation have extremely limited treatment options, which was similar to the present case [
3]. Over the past decade, the introduction of several new agents for MCL, such as bortezomib, lenalidomide, venetoclax, and ibrutinib, has yielded responses that are generally not durable beyond 2 years.
CAR T cells have shown activity in patients with r/r MCL, albeit the data are limited, and the intrapatient differences, including the costimulatory domains of CAR, conditioning chemotherapy, and cell doses, are present in CAR T-cell therapy [
10–
12]. Our case study further showed that CAR T cells induced a sustainable remission lasting 48 months in r/r MCL, which can be attributed to the long-term persistence of CAR T cells in the blood.
CAR T cell-related toxicity remains a concern [
14–
16]. Although the patient was elderly with a high tumor burden and comorbid conditions before treatment, which are known risk factors of severe toxicities caused by CAR T cells, the acute toxicities including CRS were mild and tolerated well. The patient did not require interventions with tocilizumab or corticosteroids and did not experience long-term adverse events, except for B-cell aplasia during the 48-month follow-up. This phenomenon ensured an improved quality of life compared with other currently available treatments.
In summary, this case report is the first on long-term remission lasting for greater than 4 years in a patient with MCL following CAR T-cell therapy. The CAR T-cell therapy was also tolerated well with no safety issues in this elderly patient with comorbid conditions. Hence, CAR T-cell therapy is a promising treatment option for patients with r/r MCL, and further clinical trials are needed to evaluate this strategy for these patients fully.
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