Limits...
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

Cancer regression in patients. A, Positron emission tomography (PET) images of EBV+ Hodgkin lymphoma (red arrow) and EBV− thyroid cancer (black arrow) in patient NCC-03 taken before treatment and 4, 8, and 24 weeks after infusion of EBV-specific CD8+ T cells. B, Computed tomography (CT) images of cancer tissues in the right lower leg, nasal cavity, and perirenal lesion in patient NCC-04 before treatment and 4, 24, and 36 weeks after infusion of EBV-specific CD8+ T cells. EBV+ cancer regions are indicated by red arrows.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4834812&req=5

Figure 3: Cancer regression in patients. A, Positron emission tomography (PET) images of EBV+ Hodgkin lymphoma (red arrow) and EBV− thyroid cancer (black arrow) in patient NCC-03 taken before treatment and 4, 8, and 24 weeks after infusion of EBV-specific CD8+ T cells. B, Computed tomography (CT) images of cancer tissues in the right lower leg, nasal cavity, and perirenal lesion in patient NCC-04 before treatment and 4, 24, and 36 weeks after infusion of EBV-specific CD8+ T cells. EBV+ cancer regions are indicated by red arrows.

Mentions: EBViNT was well tolerated by all patients. No DLT or treatment-related toxicities were observed. Clinical responses are shown in Table 2. At week 4 after infusion, tumor shrinkage was observed in 2 patients (NCC-03 and NCC-18) and their responses lasted for 8 weeks. Patient NCC-03 had 2 types of cancers: EBV-negative thyroid cancer and EBV-positive HL. Infusion of EBViNT resulted in the shrinkage of EBV+ HL at week 4, but HL was found in other lymph node regions from week 8 (Fig. 3A). However, EBV-negative thyroid cancer had no tumor regression during the follow-up examinations; standardized uptake value of PET image was not changed (4.4 before EBViNT infusion, 3.0 at week 4, 3.9 at week 8, and 4.2 at week 24). The results indicate that the infused EBViNT selectively recognized and lysed EBV+ cancer cells in vivo.


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)

Cancer regression in patients. A, Positron emission tomography (PET) images of EBV+ Hodgkin lymphoma (red arrow) and EBV− thyroid cancer (black arrow) in patient NCC-03 taken before treatment and 4, 8, and 24 weeks after infusion of EBV-specific CD8+ T cells. B, Computed tomography (CT) images of cancer tissues in the right lower leg, nasal cavity, and perirenal lesion in patient NCC-04 before treatment and 4, 24, and 36 weeks after infusion of EBV-specific CD8+ T cells. EBV+ cancer regions are indicated by red arrows.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Cancer regression in patients. A, Positron emission tomography (PET) images of EBV+ Hodgkin lymphoma (red arrow) and EBV− thyroid cancer (black arrow) in patient NCC-03 taken before treatment and 4, 8, and 24 weeks after infusion of EBV-specific CD8+ T cells. B, Computed tomography (CT) images of cancer tissues in the right lower leg, nasal cavity, and perirenal lesion in patient NCC-04 before treatment and 4, 24, and 36 weeks after infusion of EBV-specific CD8+ T cells. EBV+ cancer regions are indicated by red arrows.
Mentions: EBViNT was well tolerated by all patients. No DLT or treatment-related toxicities were observed. Clinical responses are shown in Table 2. At week 4 after infusion, tumor shrinkage was observed in 2 patients (NCC-03 and NCC-18) and their responses lasted for 8 weeks. Patient NCC-03 had 2 types of cancers: EBV-negative thyroid cancer and EBV-positive HL. Infusion of EBViNT resulted in the shrinkage of EBV+ HL at week 4, but HL was found in other lymph node regions from week 8 (Fig. 3A). However, EBV-negative thyroid cancer had no tumor regression during the follow-up examinations; standardized uptake value of PET image was not changed (4.4 before EBViNT infusion, 3.0 at week 4, 3.9 at week 8, and 4.2 at week 24). The results indicate that the infused EBViNT selectively recognized and lysed EBV+ cancer cells in vivo.

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