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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

CD8+ T-cell responses toward EBV/LMP2A peptides and changes of plasma Epstein Barr virus (EBV) DNA copies following EBV-induced Natural T cell (EBViNT) therapy. A, 4-1BB-expressing CD8+ T cells at day 15 in each manufactured batch of EBViNT. During the manufacturing process of EBViNT, peripheral blood mononuclear cells (PBMCs) cultured with LMP2A peptides for 14 days were restimulated with the same peptides for another 24 hours and stained with anti-4-1BB and anti-CD8 Abs at day 15. B, EBV DNA copies in patient plasma before and after EBViNT infusion.
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Figure 5: CD8+ T-cell responses toward EBV/LMP2A peptides and changes of plasma Epstein Barr virus (EBV) DNA copies following EBV-induced Natural T cell (EBViNT) therapy. A, 4-1BB-expressing CD8+ T cells at day 15 in each manufactured batch of EBViNT. During the manufacturing process of EBViNT, peripheral blood mononuclear cells (PBMCs) cultured with LMP2A peptides for 14 days were restimulated with the same peptides for another 24 hours and stained with anti-4-1BB and anti-CD8 Abs at day 15. B, EBV DNA copies in patient plasma before and after EBViNT infusion.

Mentions: EBV DNA copy number in a patient’s peripheral blood provides a measure of the tumor burden in EBV+ cancers. Although we enrolled patients with EBV+ cancers, additional tumor biopsies of the relapsed lesions were not available immediately before the EBViNT treatment in some of the patients due to the locations of their tumors. Moreover, we expected that strong CD8+ T cell responses against the EBV/LMP2A peptides in vitro would indicate that the tumor cells actively processed and presented the selected LMP2A epitopes. We were able to monitor CD8+ T-cell responses against LMP2A peptides on day 15 of in vitro culture by assessing 4-1BB+CD8+ T-cell numbers. Flow cytometric analysis indicated that the numbers of 4-1BB+CD8+ T cells reactive with LMP2A peptides differed greatly from patient to patient (Fig. 5A). Robust CD8+ T-cell responses were found in NCC-08 and NCC-17 although their clinical outcomes were poor, whereas patients NCC-03, NCC-04, and NCC-18 gave only moderate responses but underwent objective regression (Fig. 5A and Table 2).


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)

CD8+ T-cell responses toward EBV/LMP2A peptides and changes of plasma Epstein Barr virus (EBV) DNA copies following EBV-induced Natural T cell (EBViNT) therapy. A, 4-1BB-expressing CD8+ T cells at day 15 in each manufactured batch of EBViNT. During the manufacturing process of EBViNT, peripheral blood mononuclear cells (PBMCs) cultured with LMP2A peptides for 14 days were restimulated with the same peptides for another 24 hours and stained with anti-4-1BB and anti-CD8 Abs at day 15. B, EBV DNA copies in patient plasma before and after EBViNT infusion.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: CD8+ T-cell responses toward EBV/LMP2A peptides and changes of plasma Epstein Barr virus (EBV) DNA copies following EBV-induced Natural T cell (EBViNT) therapy. A, 4-1BB-expressing CD8+ T cells at day 15 in each manufactured batch of EBViNT. During the manufacturing process of EBViNT, peripheral blood mononuclear cells (PBMCs) cultured with LMP2A peptides for 14 days were restimulated with the same peptides for another 24 hours and stained with anti-4-1BB and anti-CD8 Abs at day 15. B, EBV DNA copies in patient plasma before and after EBViNT infusion.
Mentions: EBV DNA copy number in a patient’s peripheral blood provides a measure of the tumor burden in EBV+ cancers. Although we enrolled patients with EBV+ cancers, additional tumor biopsies of the relapsed lesions were not available immediately before the EBViNT treatment in some of the patients due to the locations of their tumors. Moreover, we expected that strong CD8+ T cell responses against the EBV/LMP2A peptides in vitro would indicate that the tumor cells actively processed and presented the selected LMP2A epitopes. We were able to monitor CD8+ T-cell responses against LMP2A peptides on day 15 of in vitro culture by assessing 4-1BB+CD8+ T-cell numbers. Flow cytometric analysis indicated that the numbers of 4-1BB+CD8+ T cells reactive with LMP2A peptides differed greatly from patient to patient (Fig. 5A). Robust CD8+ T-cell responses were found in NCC-08 and NCC-17 although their clinical outcomes were poor, whereas patients NCC-03, NCC-04, and NCC-18 gave only moderate responses but underwent objective regression (Fig. 5A and Table 2).

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