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Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors.

Eom HS, Choi BK, Lee Y, Lee H, Yun T, Kim YH, Lee JJ, Kwon BS - J. Immunother. (2016)

Bottom Line: Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging.By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors.The strength of the second wave was related to the efficacy of the treatment.

View Article: PubMed Central - PubMed

Affiliation: *Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center, Korea †Center for Clinical Trial, National Cancer Center, Korea ‡Cancer Immunology Branch, Division of Cancer Biology §Immune Cell Production Unit, Program for Immunotherapeutic Research, Research Institute and Hospital, National Cancer Center, Ilsandong-gu, Goyang, Gyeonggi ∥Department of Hematology-Oncology, Chonnam National University Medical School, Gwangju, Korea ¶Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.

ABSTRACT
Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy.

No MeSH data available.


Related in: MedlinePlus

TCRvβ typing of EBV-induced Natural T cell (EBViNT). TCRvβ typing was performed with the final products of EBViNT Cells using IOTest Beta Mark TCR V beta Repertoire Kit (Beckman Coulter). In brief, the cultured T cells were stained with anti-CD8-PE-Cy5 along with FITC-conjugated or PE-conjugated anti-TCRvβ mAbs. CD8+ T cells were gated and the percentages of each TCRvβ type were analyzed according to manufacturer’s instructions.
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Figure 2: TCRvβ typing of EBV-induced Natural T cell (EBViNT). TCRvβ typing was performed with the final products of EBViNT Cells using IOTest Beta Mark TCR V beta Repertoire Kit (Beckman Coulter). In brief, the cultured T cells were stained with anti-CD8-PE-Cy5 along with FITC-conjugated or PE-conjugated anti-TCRvβ mAbs. CD8+ T cells were gated and the percentages of each TCRvβ type were analyzed according to manufacturer’s instructions.

Mentions: The manufactured batches of EBViNT were suspended in sterile saline solution (DAI HAN PHARM. Co.) containing 5% human albumin (SK Chemicals) at concentrations of 3.5×106 cells/mL, and 100 mL aliquots of the suspensions were placed in infusion bags (GREEN CROSS CORP). Each batch was validated in compliance with the specifications defined in the clinical trial including: (1) absence of bacterial, fungal, mycoplasma, and viral contamination; (2) >65% of CD8+ T cells; (3) >10% of IFN-γ+ and LAMP-1+ cells among the CD8+ T cells; (4) phenotypic characterization of the CD8+ T cells using mAbs specific for CD57 (<35%), PD-1 (<20%), CD45RA (<20%), and CD45RO (>80%); (5) dominant TCRvβ type of CD8+ T cells (>20%) as analyzed using TCRvβ panel mAbs. TCRvβ typing of CD8+ T cells using PBMCs of each patient and the produced EBViNT Cells indicate that certain types of CD8+ T cells were predominantly enriched in each batch of EBViNT (Supplementary Fig. S1 and Fig. 2, Supplemental Digital Content 1, http://links.lww.com/JIT/A413).


Phase I Clinical Trial of 4-1BB-based Adoptive T-Cell Therapy for Epstein-Barr Virus (EBV)-positive Tumors.

Eom HS, Choi BK, Lee Y, Lee H, Yun T, Kim YH, Lee JJ, Kwon BS - J. Immunother. (2016)

TCRvβ typing of EBV-induced Natural T cell (EBViNT). TCRvβ typing was performed with the final products of EBViNT Cells using IOTest Beta Mark TCR V beta Repertoire Kit (Beckman Coulter). In brief, the cultured T cells were stained with anti-CD8-PE-Cy5 along with FITC-conjugated or PE-conjugated anti-TCRvβ mAbs. CD8+ T cells were gated and the percentages of each TCRvβ type were analyzed according to manufacturer’s instructions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834812&req=5

Figure 2: TCRvβ typing of EBV-induced Natural T cell (EBViNT). TCRvβ typing was performed with the final products of EBViNT Cells using IOTest Beta Mark TCR V beta Repertoire Kit (Beckman Coulter). In brief, the cultured T cells were stained with anti-CD8-PE-Cy5 along with FITC-conjugated or PE-conjugated anti-TCRvβ mAbs. CD8+ T cells were gated and the percentages of each TCRvβ type were analyzed according to manufacturer’s instructions.
Mentions: The manufactured batches of EBViNT were suspended in sterile saline solution (DAI HAN PHARM. Co.) containing 5% human albumin (SK Chemicals) at concentrations of 3.5×106 cells/mL, and 100 mL aliquots of the suspensions were placed in infusion bags (GREEN CROSS CORP). Each batch was validated in compliance with the specifications defined in the clinical trial including: (1) absence of bacterial, fungal, mycoplasma, and viral contamination; (2) >65% of CD8+ T cells; (3) >10% of IFN-γ+ and LAMP-1+ cells among the CD8+ T cells; (4) phenotypic characterization of the CD8+ T cells using mAbs specific for CD57 (<35%), PD-1 (<20%), CD45RA (<20%), and CD45RO (>80%); (5) dominant TCRvβ type of CD8+ T cells (>20%) as analyzed using TCRvβ panel mAbs. TCRvβ typing of CD8+ T cells using PBMCs of each patient and the produced EBViNT Cells indicate that certain types of CD8+ T cells were predominantly enriched in each batch of EBViNT (Supplementary Fig. S1 and Fig. 2, Supplemental Digital Content 1, http://links.lww.com/JIT/A413).

Bottom Line: Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging.By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors.The strength of the second wave was related to the efficacy of the treatment.

View Article: PubMed Central - PubMed

Affiliation: *Hematologic Oncology Clinic, Center for Specific Organs Cancer, National Cancer Center, Korea †Center for Clinical Trial, National Cancer Center, Korea ‡Cancer Immunology Branch, Division of Cancer Biology §Immune Cell Production Unit, Program for Immunotherapeutic Research, Research Institute and Hospital, National Cancer Center, Ilsandong-gu, Goyang, Gyeonggi ∥Department of Hematology-Oncology, Chonnam National University Medical School, Gwangju, Korea ¶Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA.

ABSTRACT
Although adoptive cell therapy using Ag-specific T cells has been tested successfully in the clinic, the production of these T cells has been challenging. By applying our simple and practical 4-1BB-based method for the generation of Ag-specific CD8 T cells, here we determined the maximum tolerated dose, toxicity profile, immunologic responses, and clinical efficacy of autologous Epstein-Barr virus (EBV)/LMP2A-specific CD8 T cells (EBV-induced Natural T cell; EBViNT) in patients with relapsed/refractory EBV-positive tumors. This was a single-center, phase I, dose-escalation trial study evaluating 4 escalating dosing schedules of single injected EBViNT. CD8 T-cell responses against different LMP2A peptides in each patient were determined, and the most effective peptides were used to produce EBViNT. The produced autologous EBViNTs were single infused to patients with EBV-associated malignancy who had failed to standard treatments and were of HLA-A02 or A24 type. Of 11 patients enrolled, 8 patients received a single infusion of EBViNT: 4 with nasopharyngeal carcinomas, 1 with Hodgkin lymphoma, 2 with extranodal NK/T lymphomas, and 1 with diffuse large B-cell lymphoma. Single infusion of EBViNT was well tolerated by all the patients and generated objective antitumor responses in 3 of them. EBViNT infusion induced 2 waves of interferon-γ response: 1 approximately 1 week and the other 4-8 weeks after the treatment. The strength of the second wave was related to the efficacy of the treatment. The current trial shows that EBViNT therapy is safe and may provide a new option for treating EBV-positive recurrent cancer patients resistant to conventional therapy.

No MeSH data available.


Related in: MedlinePlus