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Autologous cytotoxic T lymphocyte therapy was effective for M-VAC-refractory invasive bladder cancer

In the present study, we performed CTL therapy in a patient with metastatic bladder cancer, who had relapsed after M-VAC therapy.


Authors: Kogenta Nakamura MD, PhD1; Kazuhiro Yoshikawa PhD2; Yoshiaki Yamada MD, PhD1; Makoto Sumitomo MD, PhD1

1 Department of Urology, Aichi Medical University School of Medicine
2 Cell Therapy Center, Aichi Medical University Hospital

Corresponding Author: Kogenta Nakamura, MD, PhD, Department of Urology, Aichi Medical University School of Medicine. Nagakute-cho, Aichi 480-1195, Japan. Tel: +81-561-62-3311   E-mail address: [email protected]


A report on the efficacy of CTL therapy for urogenital cancer already exists in the literature.1 In the present study, we performed CTL therapy in a patient with metastatic bladder cancer, who had relapsed after M-VAC therapy.


Standard chemotherapy for invasive bladder cancer with metastases includes M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) and GC (gemcitabine and cisplatin).2 Many chemotherapeutic regimens have been used as second-line treatment, but no regimen surpasses M-VAC and GC.  There are high expectations for taxanes and other similar drugs, and the results of a large-scale, randomized trial are awaited.
Autologous cytotoxic T lymphocyte (CTL) therapy using autologous tumor tissue is a technique in which autologous lymphocytes collected from the peripheral blood and an autologous tumor irradiated with γ-rays are cultured in vitro in the presence of interleukin-2 (IL-2), and anti-CD3 for induction and proliferation of killer cells that are expected to be specific to the tumor, and then the killer cells are aseptically returned to the body.  For this therapy, it is essential that MHC-class I antigen is expressed on tumor cells.


Case report
We performed total cystectomy with periaortic and pelvic lymphadenectomy, and bilateral cutaneous ureterostomy in a 61 year old Japanese male patient with a diagnosis of T4N2M0 bladder cancer made 6 years previously.  We chose  to perform urinary diversion to cutaneous ureterostomy instead of ileal conduit, to avoid intestinal complications and also because we wished to start systemic chemotherapy as soon as possible. Pathological examination revealed urothelial carcinoma, grade G3, pT4. The right external iliac lymph nodes, bilateral obturator lymph nodes and aortocaval lymph nodes were positive.  Since the patient subsequently developed enlarged mediastinal, supraclavicular and para-aortic lymph nodes (Figure 1a), three courses of M-VAC therapy were performed in combination with mild hyperthermia, which is known to lead to fewer adverse reactions.3  The efficacy of the chemotherapy was evaluated using the Response Evaluation Criteria In Solid Tumor classification.  CT scan, after completion of three courses of M-VAC therapy, revealed that the mediastinal lymph nodes and the right supraclavicular lymph nodes had disappeared and the para-aortic lymph nodes were reduced in size.  Since CT scan subsequently showed enlarged para-aortic lymph nodes, two further courses of M-VAC therapy were performed.  However, the para-aortic lymph nodes remained unchanged (Figure 1b).
After approval was obtained from the institutional review board of our hospital (# 152), four courses of CTL therapy in combination with IFN-γ and IL-2 administration were initiated (at intervals of two weeks) after surgery.  Two days before administration, 200 mg/body of Endoxan was administered by intravenous infusion.  An average of 22.6  108 cells were administered.  During each course, blood was collected on the day after administration to examine whether the CD8 level had increased or not.  After completion of four courses of treatment, a CT scan was performed and revealed a partial response (PR) of the para-aortic lymph nodes (Figure 1 c).


Figure 1 (a) Computed tomography showing enlargement of para-aortic lymph nodes before M-VAC therapy.


(B) Computed tomography showing para-aortic lymph nodes remaining unchanged after M-VAC therapy.


(C) Computed tomography showing reduced para-aortic lymph node size after CTL therapy.  The lymph node size deceased from 15 to 8 mm.


At present, 71 months after completion of CTL therapy, the patient has had recurrence and has maintained his PR status.


Autologous CTL therapy did not cause any adverse reactions in our patient.  It is suggested that this therapy can be performed safely and should also be considered for cases of progressive bladder cancer with metastasis.


1 Kawai K, Saijo K, Oikawa T et al : Clinical course and immune response of a renal cell carcinoma patient to adoptive transfer of autologous cytotoxic T lymphocytes. Clin Exp Immunol 2003; 134: 264-269.
2 von der Maase H, Sengelov L, Roberts JT et al : Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23: 4602-4608.
3 Yamada Y, Itoh Y, Aoki S et al. Preliminary results of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced or metastatic transitional cell carcinoma of the urothelium. Cancer Chemother Pharmacol 2009; 64: 1079-1083.


Date added to 02/02/2012

DOI: 10.1002/BJUIw-2011-059-web

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