Treatment of CD20-directed Chimeric Antigen Receptor-modified T cells in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an early phase IIa trial report

Wen-Ying Zhang, Yao Wang, Ye-Lei Guo, Han-Ren Dai, Qing-Ming Yang, Ya-Jing Zhang, Yan Zhang, Mei-Xia Chen, Chun-Meng Wang, Kai-Chao Feng, Su-Xia Li, Yang Liu, Feng-Xia Shi, Can Luo, Wei-Dong Han, Wen-Ying Zhang, Yao Wang, Ye-Lei Guo, Han-Ren Dai, Qing-Ming Yang, Ya-Jing Zhang, Yan Zhang, Mei-Xia Chen, Chun-Meng Wang, Kai-Chao Feng, Su-Xia Li, Yang Liu, Feng-Xia Shi, Can Luo, Wei-Dong Han

Abstract

Patients with relapsed or refractory non-Hodgkin lymphoma have a dismal prognosis. Chimeric Antigen Receptor (CAR)-modified T cells (CART cells) that targeted CD20 were effective in a phase I clinical trial for patients with advanced B-cell lymphomas. We performed a phase IIa trial to further assess the safety and efficacy of administering autologous anti-CD20 CART (CART-20) cells to patients with refractory or relapsed CD20+ B-cell lymphoma. Eleven patients were enrolled, and seven patients underwent cytoreductive chemotherapy to debulk the tumors and deplete the lymphocytes before receiving T-cell infusions. The overall objective response rate was 9 of 11 (81.8%), with 6 complete remissions (CRs) and 3 partial remissions; no severe toxicity was observed. The median progression-free survival lasted for >6 months, and 1 patient had a 27-month continuous CR. A significant inverse correlation between the levels of the CAR gene and disease recurrence or progression was observed. Clinically, the lesions in special sites, specifically the spleen and testicle, were refractory to CART-20 treatment. Collectively, these results together with our data from phase I strongly demonstrated the feasibility and efficacy of CART-20 treatment in lymphomas and suggest large-scale patient recruitment in a future study. This study was registered at www.clinicaltrials.org as NCT01735604.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Clinical protocol design. Patients with tumors that had a diameter

Figure 2

Clinical responses of all patients.…

Figure 2

Clinical responses of all patients. ( a ) The progression-free survival (PFS) for…

Figure 2
Clinical responses of all patients. (a) The progression-free survival (PFS) for all participating patients. More than 50% of the patients achieved a 6-month PFS. (b, c) The positron emission tomography-computed tomography (PET-CT) images of patients UPN03 and UPN07, respectively. The higher uptake in the cervical lymph node of UPN03 disappeared at the 3-month time point after the Chimeric Antigen Receptor-modified T-20 (CART-20) cell infusion. The lesions of patient UPN07 at the mediastinum and groin disappeared at the 6-month time point after the CART-20 cell infusion. (d) The time of progression-free survival after the CART-20 cell infusions was significantly longer than that observed after the last salvage chemotherapies. The light brown bars denote responses after salvage chemotherapy; the dark brown bars demonstrate the PFS after the CART-20 cell infusion.

Figure 3

Characteristics and influential factors of…

Figure 3

Characteristics and influential factors of expansion of the Chimeric Antigen Receptor-modified T-20 (CART-20)…

Figure 3
Characteristics and influential factors of expansion of the Chimeric Antigen Receptor-modified T-20 (CART-20) cells in vivo. (a) The time course shows that the peak levels of the CART-20 cells detected by qRT-PCR were observed at approximately 4 weeks after infusion and gradually decreased thereafter. (b) Detection of CART-20 cells at 1 week and 4 weeks after infusion was independent of the infused T-cell dose. (c) A copy number less than 200 (no./mg gDNA) was regarded as CART-20 cell negative. The last observance of positive CART-20 cells was independent of the absolute effects of memory and central memory T cells.

Figure 4

The numbers of CD20 +…

Figure 4

The numbers of CD20 + lymphocyte cells by flow cytometry and the copy…

Figure 4
The numbers of CD20+ lymphocyte cells by flow cytometry and the copy numbers of Chimeric Antigen Receptor (CAR) molecules by quantitative real-time-PCR in the peripheral blood of relapsed patients after Chimeric Antigen Receptor-modified T-20 (CART-20) cell infusion. Relapses occurred after the numbers of copies dropped and the numbers of B cells increased. An ↓ indicates the time of relapse.

Figure 5

Responses of the special lesions…

Figure 5

Responses of the special lesions to Chimeric Antigen Receptor-modified T-20 (CART-20) cells. (…

Figure 5
Responses of the special lesions to Chimeric Antigen Receptor-modified T-20 (CART-20) cells. (a) The skin lesions of patient UPN09 completely disappeared, and the disappearance lasted up to 10 months or more, despite continued splenomegaly. (b) The new lesions in the testes of patient UPN02 emerged at 6 months after infusion. (c) Immunohistochemical examination of a needle biopsy of lesions in the testis from patient UPN02 at 6 months after CART-20 cell infusion showed that the tumor cells were CD20+, CD3−, CD4−, and CD8−. (d) The CART-20 cells in the peripheral blood, cerebral spinal fluid (CSF) and the testis of patient UPN02 were measured by quantitative real-time-PCR at 6 months after CART-20 cell infusion. PB, peripheral blood cells.
Figure 2
Figure 2
Clinical responses of all patients. (a) The progression-free survival (PFS) for all participating patients. More than 50% of the patients achieved a 6-month PFS. (b, c) The positron emission tomography-computed tomography (PET-CT) images of patients UPN03 and UPN07, respectively. The higher uptake in the cervical lymph node of UPN03 disappeared at the 3-month time point after the Chimeric Antigen Receptor-modified T-20 (CART-20) cell infusion. The lesions of patient UPN07 at the mediastinum and groin disappeared at the 6-month time point after the CART-20 cell infusion. (d) The time of progression-free survival after the CART-20 cell infusions was significantly longer than that observed after the last salvage chemotherapies. The light brown bars denote responses after salvage chemotherapy; the dark brown bars demonstrate the PFS after the CART-20 cell infusion.
Figure 3
Figure 3
Characteristics and influential factors of expansion of the Chimeric Antigen Receptor-modified T-20 (CART-20) cells in vivo. (a) The time course shows that the peak levels of the CART-20 cells detected by qRT-PCR were observed at approximately 4 weeks after infusion and gradually decreased thereafter. (b) Detection of CART-20 cells at 1 week and 4 weeks after infusion was independent of the infused T-cell dose. (c) A copy number less than 200 (no./mg gDNA) was regarded as CART-20 cell negative. The last observance of positive CART-20 cells was independent of the absolute effects of memory and central memory T cells.
Figure 4
Figure 4
The numbers of CD20+ lymphocyte cells by flow cytometry and the copy numbers of Chimeric Antigen Receptor (CAR) molecules by quantitative real-time-PCR in the peripheral blood of relapsed patients after Chimeric Antigen Receptor-modified T-20 (CART-20) cell infusion. Relapses occurred after the numbers of copies dropped and the numbers of B cells increased. An ↓ indicates the time of relapse.
Figure 5
Figure 5
Responses of the special lesions to Chimeric Antigen Receptor-modified T-20 (CART-20) cells. (a) The skin lesions of patient UPN09 completely disappeared, and the disappearance lasted up to 10 months or more, despite continued splenomegaly. (b) The new lesions in the testes of patient UPN02 emerged at 6 months after infusion. (c) Immunohistochemical examination of a needle biopsy of lesions in the testis from patient UPN02 at 6 months after CART-20 cell infusion showed that the tumor cells were CD20+, CD3−, CD4−, and CD8−. (d) The CART-20 cells in the peripheral blood, cerebral spinal fluid (CSF) and the testis of patient UPN02 were measured by quantitative real-time-PCR at 6 months after CART-20 cell infusion. PB, peripheral blood cells.

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