Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

2022, vol. 31, nr 3, March, p. 327–335

doi: 10.17219/acem/145948

Publication type: research letter

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Mu J, Liu M, Wang J, et al. Successful treatment of second-time CAR-T 19 therapy after failure of first-time CAR-T 19 and ibrutinib therapy in relapsed mantle cell lymphoma. Adv Clin Exp Med. 2022;31(3):327–335. doi:10.17219/acem/145948

Successful treatment of second-time CAR-T 19 therapy after failure of first-time CAR-T 19 and ibrutinib therapy in relapsed mantle cell lymphoma

Juan Mu1,A,B,C,E,F, Meijing Liu1,C,E,F, Jia Wang1,A,B,F, Juanxia Meng1,A,F, Rui Zhang1,B,C,F, Yanyu Jiang1,C,E,F, Qi Deng1,A,B,C,D,F

1 Department of Hematology, Tianjin First Central Hospital, School of Medicine, Nankai University, China

Abstract

Background. A patient with relapsed mantle cell lymphoma (MCL) showed stable disease after receiving ibrutinib therapy as a salvage therapy, after the failure of his first chimeric antigen receptor (CAR)-T 19 cell therapy.

Objectives. The combined effects of CAR-T 19 cells from the patient and ibrutinib on JeKo-1 cell were explored in vitro and in vivo.

Materials and methods. The expression of programmed death-1 (PD-1) receptor on CD3+ T cells in the peripheral blood decreased from 82.95% in the first CAR-T 19 cell therapy to approx. 40% after 14 months of ibrutinib therapy. When the disease progressed again during the ibrutinib therapy, the patient was enrolled into the same clinical trial of CAR-T 19 cell therapy.

Results. The efficacy of CAR-T 19 cells increased after the ibrutinib therapy. The mRNA expression level of PD-1 in CAR-T 19 cells after ibrutinib therapy was lower than in CAR-T 19 cells before the ibrutinib therapy. Nevertheless, CAR-T 19 cell therapy combined with ibrutinib had no synergistic effect in a short term in vitro and in the JeKo-1 cell mouse model.

Conclusions. We expect our results to provide evidence for the combination treatment of ibrutinib for MCL or even other types of B-cell lymphomas. Moreover, the improvement in CAR-T 19 cell function was based on long-term ibrutinib therapy.

Key words: chimeric antigen receptor, immunotherapy, lymphoma, clinical chimeric antigen receptor T cell trials, ibrutinib

Background

Relapsed/refractory (R/R) B-cell non-Hodgkin’s lymphoma (B-NHL) is usually characterized by poor prognosis.1, 2 Chimeric antigen receptor (CAR) T-cell therapy has shown to be more effective in patients with R/R B-cell acute lymphoblastic leukemia (B-ALL)3, 4, 5, 6, 7, 8, 9 and R/R B-NHL.10, 11, 12, 13 However, patients with R/R B-NHL have lower complete remission (CR) rate of CD19 CAR T–cell (CAR-T 19) therapy than those with R/R B-ALL.14, 15

Ibrutinib, as an inhibitor of Bruton’s tyrosine kinase (BTK), has been approved by the US Food and Drug Administration (FDA) for the treatment of relapsed chronic lymphocytic leukemia (CLL)16 and mantle cell lymphoma (MCL).17 This drug has been extensively administered for the treatment of various B-cell lymphomas.18, 19, 20 Bruton’s tyrosine kinase expressed on B cells acts as a cytoplasmic tyrosine kinase in the B-cell receptor signaling pathway.21, 22 Ibrutinib blocks BTK activation in different pathways to inhibit B-cell receptor signaling in B-cell lymphomas.23, 24, 25

The combination of ibrutinib and CAR-T 19 cells has shown excellent results in preclinical and clinical studies.26 The CAR-T 19 cell therapy has been proven to be highly effective in CLL patients who have previously taken ibrutinib.27 This drug can enhance the engraftment and efficacy of CAR-T 19 cells in CLL patients.28 Other clinical reports have indicated a promising antitumor activity of CAR-T 19 cells in CLL patients who are resistant to ibrutinib therapy.29 Ibrutinib combined with CAR-T 19 cells has been studied in an MCL cell line.30 The efficacies of CAR-T 19 cells on the MCL cell line in vitro and in vivo were enhanced by this drug. In this study, a patient with relapsed MCL obtained CR with his second CAR-T 19 cell therapy after the failure of the first CAR-T 19 cell therapy and 14 months of ibrutinib therapy. The combination of CAR-T 19 cells from the patient and ibrutinib on JeKo-1 cell was explored in vitro and in vivo.

Objectives

The aim of the study was to observe whether a long-term ibrutinib therapy could enhance the efficacy of CAR-T 19 cell therapy in the treatment of R/R MCL in vitro, in mice, and clinically.

Materials and methods

Medical history

A 58-year-old man experienced right epigastric pain for 3 days in September 2014. Abdominal computed tomography (CT) revealed the presence of multiple low-density shadows in the spleen and lymph nodes of the splenic portal area/retroperitoneum (Figure 1A). The biopsy of the hilum of the lymph node and immunohistochemical examination confirmed the diagnosis of MCL (Figure 1B). The cyclin D1 level was 72.5%. The CR was obtained after 6 cycles of R-CHOP combination chemotherapy. No autologous hematopoietic stem cell transplantation or other maintenance therapy was initiated due to lung injury caused by heart stent surgery and rituximab.

In February 2017, the patient was again admitted to our hospital owing to lymph node enlargement in the right neck. There were no immunoglobulin H (IgH) and T-cell receptor gene rearrangements (Figure 1C). Neck CT revealed that multiple cervical lymph nodes were enlarged (Figure 2A). Cervical lymph node biopsy confirmed the previous diagnosis of MCL (Figure 1D). The cyclin D1 level was 69.2%. Owing to the complications, the patient could not receive further combination chemotherapy. Subsequently, he participated in a clinical trial of autologous CAR-T 19 cells, expressing murine anti-CD19 scFv and 4-1BB-CD3ζ costimulatory activation domain (ChiCTR-ONN-16009862). The patient provided informed consent prior to the enrollment. This clinical trial was conducted under the approval of the Medical Ethics Committee of Tianjin First Central Hospital, China (approval No. 2015002X). Lymphodepleting chemotherapy with fludarabine (30 mg/m2) and cyclophosphamide (400 mg/m2) was given to the patient from the day −4 to day −2. On day 0, the patient was infused with autologous CAR-T 19 cells (2 × 107 cells/kg). The patient had high fever, chills and headache in the first 3 days. At day 7 of the treatment, the cervical lymph node enlargement suddenly increased with laryngeal edema and obstructive dyspnea (Figure 2B). Therefore, we were forced to terminate CAR-T 19 cell therapy; the laryngeal edema and obstructive dyspnea were treated using dexamethasone.

Two weeks after the failure of CAR-T 19 cells therapy, ibrutinib therapy was administered as the salvage therapy. No increase was found in the percentage of anti-CAR-T 19 cells and gene expression level of anti-CD19 CAR. After ibrutinib therapy for 2 months, the size of the cervical lymph node decreased. Meanwhile, the programmed death-1 (PD-1) expression in peripheral blood CD3+ T cells was 82.95%. In the following 2 months, no increase was observed in the percentage of anti-CAR-T 19 cells as well as gene expression level of anti-CD19 CAR in the peripheral blood. Therefore, the patient continued ibrutinib therapy for approx. 14 months with a stable disease condition.

Successful second CAR-T 19 cell therapy

After ibrutinib treatment for 14 months, cervical lymph node enlargement was observed again (Figure 2C). Nevertheless, the PD-1 expression decreased to 42.5% at this time. As a result, the patient was once again enrolled in the same clinical trial (ChiCTR-ONN-16009862). He received the same dose of lymphodepleting chemotherapy and autologous CAR-T 19 cells as the 1st CAR-T 19 cell therapy. The level of interleukin-6 (IL-6) was measured using electrochemiluminescence analysis. Flow cytometry was used to detect the level of PD-1 in CD3+ T cells and the percentage of CAR-T 19 cells in peripheral blood. The gene expression level of CAR-T 19 was determined using quantitative polymerase chain reaction (qPCR).

CAR-T 19 cell proliferation, cytotoxicity and mRNA expression level of PD-1

The CAR-T 19 cells from the patient’s CD3+ T cells were divided into various groups: the CAR-T 19 cell group derived from the patient before ibrutinib therapy with or without ibrutinib and CAR-T 19 cell group after ibrutinib therapy with or without ibrutinib. Ibrutinib (4 μg/mL/day) was added to the CAR-T 19 cell culture system on the first day. Cell Counting Kit-8 (Dojindo Molecular Technologies, Kumamoto, Japan) was used to detect the CAR-T 19 cell proliferation at 0 h, 24 h and 48 h. The transfection efficiency of CAR-T 19 cells was analyzed using flow cytometry. The JeKo-1 cell line was bought from the American Type Culture Collection (ATCC; Manassas, USA). Each group of CAR-T 19 and JeKo-1 cells was cocultured in a 1:1 ratio for 48 h without adding cytokines. The lactate dehydrogenase cytotoxicity test kit was used for the measurement of cytotoxicity at 0 h, 24 h and 48 h; the detection was performed at a wavelength of 490 nm. The enzyme-linked immunosorbent assay (ELISA) kit (Becton Dickinson Biosciences, Franklin Lakes, USA) was applied to determine the release of tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). The absorbance (A) at 0 h, 12 h, 24 h, and 48 h was measured at 450 nm. The PD-1 mRNA expression in CAR-T 19 cells was determined with reverse transcription (RT)-qPCR. The PD-1 expression, normalized to that of GAPDH and relative to a calibrator, was calculated using the 2−ΔΔCt method. All experiments were repeated 3 times to calculate the mean values.

Comparison of the efficacy
of CAR-T cell therapy before
and after ibrutinib therapy in mice

Each procedure was performed under the approval of the Animal Care and Use Committee of the Ethics Committee of Nankai University, Tianjin, China (approval No. 2017-000012). In a lymphoma animal mode, 6–8 weeks old female mice (CAnN.Cg-Foxn1nu/CrlVR) bought from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China), were injected with 1 × 107 JeKo-1 cells through caudal vein. After 10 days, the successful establishment of the model was confirmed with flow cytometry of the peripheral blood of mice. The mice of lymphoma model were randomly divided into different groups and treated with CAR-T 19 cells (1 × 107/kg), with or without ibrutinib. The ibrutinib monotherapy group was used as the control group. On the first day of treatment, CAR-T 19 cells were administered through caudal vein. Mice were given the clinically recommended dose of ibrutinib (8 mg/kg/day) via oral gavage. Each group consisted of 5 mice. The proportion of JeKo-1 and CAR-T 19 cells in mice was determined with flow cytometry.

Statistical analysis

Data are expressed as mean ± standard error (SE), along with the number of repeated experiments. All data were independently analyzed using the t-test. Statistically significant difference was defined as p < 0.05.

Results

Results of the second CAR-T 19 cell therapy

We obtained the agreement from the patient for using their specimens and data in this study. The patient had high fever, chills and headache during the first 5 days following the 2nd CAR-T 19 cell therapy. The highest serum IL-6 level was 275.6 pg/mL on day 4 of the 2nd treatment, compared with 15.2 pg/mL on the same day of the 1st treatment (Figure 3A). The expression level of PD-1 was maintained at >80% in the 1st treatment, in the 2nd treatment, it was maintained at approx. 40% (Figure 3B).

On day 7 of the 2nd treatment, the percentage of CAR-T 19 cells was the highest (7.52%) in CD3+ T cells (Figure 3C). Compared with the highest CAR-T 19 DNA value of 280 copies/µg DNA obtained in the 1st treatment, the value was 4730 copies/µg DNA in the 2nd treatment (Figure 3D). The changes in serum ferritin and C-reactive protein (CRP) levels were similar to those in IL-6 levels (Figure 3E,F).

In the 2nd treatment, the size of the cervical lymph node was significantly reduced with grade II CRS31 after the 2nd CAR-T 19 cell therapy (Figure 2D). The patient achieved CR after 2 months; CR has been maintained for 15 months, up to the present.

Results in vitro

No significant difference of the transfection rate was found in the 4 groups (p = 0.6572) (Figure 4A). There was also no difference of the proliferation in the 4 groups at 24 h or 48 h (p24h = 0.3660 and p48h = 0.2061) (Figure 4B). Ibrutinib therapy for 14 months and the addition of ibrutinib into the culture system did not affect the proliferation and transfection of CAR-T 19 cells. The CAR-T 19 cells derived from T cells before or after ibrutinib therapy showed almost no change in JeKo-1 cell cytotoxicity, regardless of whether ibrutinib was present or not in the culture system. Ibrutinib alone was used as the control group (before ibrutinib therapy: p24h = 0.8770 and p48h = 0.4923; after ibrutinib therapy: p24h = 0.5871 and p48h = 0.6969). The CAR-T 19 cells after ibrutinib therapy showed significant JeKo-1 cell activity regardless of whether ibrutinib was present or not in the culture system (without ibrutinib in the culture: p24h = 0.0000 and p48h = 0.0000; with ibrutinib in the culture: p24h = 0.0000 and p48h = 0.0000) (Figure 4C). There was no difference in the IFN-γ release profile of all groups (p24h = 0.4006 and p48h = 0.5819) (Figure 4D). Similarly to the results of proliferation and transfection, ibrutinib therapy and the addition of ibrutinib into the culture system did not affect the IFN-γ release. After ibrutinib therapy, PD-1 mRNA expression in CAR-T 19 cells was lower than before ibrutinib therapy (without ibrutinib in the culture: p = 0.0013; with ibrutinib in the culture: p = 0.0052). The mRNA expression level of PD-1 exhibited no difference in the CAR-T 19 cell culture systems with or without ibrutinib (before ibrutinib therapy: p = 0.2104; after ibrutinib therapy: p = 0.1036) (Figure 5).

Results in mice

In the animal experiments, the percentage of JeKo-1 cells decreased in the CAR-T 19 cell group after ibrutinib therapy with ibrutinib compared with that before ibrutinib therapy with ibrutinib on 14 days and 28 days after therapy (p14days = 0.0000 and p28days = 0.0000). The percentage of JeKo-1 cells decreased in the CAR-T 19 cell group after ibrutinib therapy compared with that before ibrutinib therapy on 14 days after therapy (p14days = 0.0000). Nevertheless, no difference was found in the two CAR-T 19 cell groups after ibrutinib therapy at 14 days or 28 days after CAR-T 19 cell therapy (p14days = 0.1459 and p28days = 0.4005). The proportion of JeKo-1 cells in the group of CAR-T 19 cells rapidly increased before ibrutinib therapy, resulting in the immediate death of the mice after 14 days, compared with that in the group treated with ibrutinib (p14days = 0.0021). Both ibrutinib and CAR-T groups exhibited no difference, which was combined with ibrutinib before ibrutinib therapy (p14days = 0.4292 and p28days = 0.3175). The percentage of JeKo-1 cells in the CAR-T 19 cell groups after ibrutinib therapy combined with ibrutinib was lower than in the ibrutinib group (p14days = 0.0000 and p28days = 0.0000) (Figure 6A). The proportion of CAR-T 19 cells in the CAR-T 19 cell groups after ibrutinib therapy with ibrutinib (p14days = 0.0000) or without ibrutinib (p14days = 0.0000) was higher than before ibrutinib therapy, but no difference was found in the two CAR-T 19 cell groups after ibrutinib therapy (p14days = 0.1922 and p28days = 0.4490). Besides, the proportion in the CAR-T 19 cell group exhibited no difference before ibrutinib therapy with or without ibrutinib (p14days = 0.3514) (Figure 6B).

Discussion

In our study, the patient with relapsed MCL showed stable disease during his 14-month ibrutinib treatment after the 1st therapy failed. When his condition worsened again during ibrutinib treatment, he received the 2nd CAR-T 19 cell therapy to achieve CR. The reason for the failure of the 1st CAR-T 19 cell therapy was unclear. It was observed that PD-1 expression was 82.95% in CD3+ T cells before the first CAR-T 19 therapy. Interestingly, it decreased to approx. 40% after the 14-month ibrutinib therapy. This research investigated the efficacy of CAR-T 19 cell therapy before and after ibrutinib therapy in vitro and in mice.

Ibrutinib functions as a BTK inhibitor to downregulate NF-кB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling, thus controlling the homing and migration of tumor cells. Blocking the interaction between macrophages and tumor cells is an important way to decrease the chemoattraction of tumor cells to the bone marrow microenvironment.32, 33, 34, 35 In one study, ibrutinib therapy with CLL for >5 months increased the proliferation and efficacy of CAR-T 19 cells.28 A long-term ibrutinib therapy for patients with CLL could result in overcoming the immunosuppression of the primary disease, repairing the functional defects of autologous T cells, and decreasing the PD-1 expression in T cells. This effect of ibrutinib therapy is achieved through BTK-dependent and BTK-independent mechanisms.36

Another research has shown that ibrutinib modulates the tumor microenvironment of patients with CLL through the downregulation of the expression level of programmed death ligand-1 in CLL cells after 3 months of ibrutinib therapy.37 Therefore, although the resistance to ibrutinib might occur during the treatment,38, 39 the CAR-T 19 cell therapy was highly effective in CLL patients after the failure of ibrutinib therapy.

Does long-term ibrutinib therapy improve T-cell function in patients with CLL and other types of B-cell lymphomas? The combination of ibrutinib improved the therapeutic effect of CAR-T 19 cell therapy on MCL cell line in vitro and in vivo.30 In our study, the patient with relapsed MCL achieved CR with the 2nd CAR-T 19 cell therapy after 14-month ibrutinib therapy.

Limitations

This study has some limitations. The study did not investigate whether the mechanism of improving the T-cell function in MCL patients following long-term ibrutinib therapy is consistent with that in patients with CLL, and whether long-term ibrutinib therapy improves T-cell function in other types of B-cell lymphomas, which will be explored in the further studies.

Conclusions

In our study, we demonstrated that the efficacy of CAR-T 19 cell therapy was enhanced after 14-month ibrutinib therapy in vitro, in mice and in the clinical trial in which a patient was enrolled. However, there was no synergistic effect of a short period of combination of CAR-T 19 cells and ibrutinib in vitro and in mice. The results of our study support the conclusion that long-term ibrutinib therapy could enhance the efficacy of the CAR-T 19 cell therapy. These results in MCL cell lines and the patient with MCL are similar to those of previous studies on CLL cell lines and patients with CLL.28

Figures


Fig. 1. Diagnosis of mantle cell lymphoma. A. Abdominal computed tomography (CT) in May 2014; B. Result of the pathological biopsy in May 2014; C. Immunoglobulin H (IgH) and T-cell receptor gene rearrangements were negative; D. Result of the pathological biopsy in February 2017
Fig. 2. Changes in the lymph nodes in the 2 chimeric antigen receptor (CAR)-T 19 cell therapies. A. Neck computed tomography (CT) before the first therapy; B. Enlargement of cervical lymph node after the 1st therapy; C. The cervical lymph node increased in size again after ibrutinib therapy; D. The size of the cervical lymph node returned to normal after the 2nd CAR-T 19 cell therapy
Fig. 3. Comparison of the 2 chimeric antigen receptor (CAR)-T 19 cell therapies. A. The highest serum interleukin-6 (IL-6) level was 275.6 pg/mL in the 2nd therapy; B. The programmed death-1 (PD-1) expression decreased from approx. 80% in the 1st therapy to approx. 40% in the 2nd therapy; C. The highest percentage of CAR-T 19 cells was 7.52% in the 2nd therapy; D. The highest copy number of CAR-T 19 DNA was 4730 copies/µg DNA in the 2nd therapy; E. The highest C-reactive protein (CRP) level was 139.5 mg/mL in the 2nd therapy; F. The highest ferritin level was 355.4 ng/mL in the 2nd therapy
Fig. 4. Cytotoxicity of all chimeric antigen receptor (CAR)-T 19 cell groups to lymphoma cells. A,B. No significant difference was found in the transfection and proliferation of cells in all groups; C. The CAR-T 19 cells derived from T cells before or after ibrutinib therapy showed almost no change in JeKo-1 cell cytotoxicity regardless of whether ibrutinib was present or not. The CAR-T 19 cells after ibrutinib therapy showed significant JeKo-1 cell activity; D. There was no difference in the interferon gamma (IFN-γ) release profile in all groups
Fig. 5. The programmed death-1 (PD-1) mRNA expression in chimeric antigen receptor (CAR)-T 19 cells. The PD-1 mRNA expression in CAR-T 19 cells after ibrutinib therapy was lower than that before ibrutinib therapy. However, it showed no difference in the before or after ibrutinib therapy groups, regardless of whether ibrutinib was present or not in the system
Fig. 6. Proportion of lymphoma and chimeric antigen receptor (CAR)-T 19 cells in mice. A. Regardless of whether ibrutinib was administered at the same time or not, the percentage of JeKo-1 cells in mice significantly decreased in the group of CAR-T 19 cell after ibrutinib treatment. The proportion of JeKo-1 cells in mice rapidly increased in the group of CAR-T 19 cell before ibrutinib treatment, leading to the immediate death of the mice after 14 days; B. The proportion of CAR-T 19 cells showed an inverse relationship with the proportion of JeKo-1 cells

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