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Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)

Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)
Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)
Background: In the UK almost 7000 people are diagnosed with leukaemia each year, but despite continuing advances in diagnosis and treatment with new drugs, such as the tyrosine kinase inhibitors, the majority of these patients will eventually die from their disease. Until quite recently, the only treatment to offer the possibility of long-term disease-free survival was allogeneic stem cell transplantation. However, this carries a substantial risk of mortality and is available to only a minority of patients.

Objectives: The aim of the study was to test the hypothesis that molecular and clinical responses, induced by T lymphocytes (T cells), can be predicted by increases in the number of CD8+ (cluster of differentiation 8-positive) T cells specific for the vaccine-encoded T-cell epitopes. This project also aimed to build on the established programme of deoxyribonucleic acid (DNA) fusion-gene vaccination delivered by intramuscular injection, exploiting a unique experience with electroporation, to induce durable immune responses with the aim of controlling disease by precision attack of the tumour by CD8+ T cells.

Method: A non-randomised, open-label, single-dose-level Phase II clinical trial in two patient groups [chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML)] on stable doses of imatinib. Human leucocyte antigen A2-positive (HLA A2+) patients were vaccinated with two DNA vaccines: (1) p.DOM–WT1-37 (epitope sequence: VLDFAPPGA); and (2) p.DOM–WT1-126 (epitope sequence: RMFPNAPYL). The HLA A2-negative patients formed an unvaccinated control group. The sample size for the HLA A2+ group was originally determined following Simon’s optimal Phase II trial design (Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10). This was changed to A’Hern’s single-stage design during the course of the trial (A’Hern RP. Sample size tables for single-stage phase II designs. Stat Med 2001;20:859–66), which was endorsed by the trial’s independent oversight committees.

Results: The study included 12 patients with CML who were vaccinated and nine patients with CML who were unvaccinated as the control group. Both the vaccines and the electroporation were safe, with no new or unexpected toxicities. The evaluation adverse events of special interest (heart, bone marrow, renal) did not reveal safety concerns. Two BCR–ABL (breakpoint cluster region–Abelson murine leukaemia viral oncogene homolog 1) responses were observed, both of which were defined as a major response, with one in each group. Two Wilms’ tumour antigen 1 (WT1) molecular responses were observed in the vaccinated group and one was observed in the control group. At an immunological level, the vaccine performed as expected.

Conclusions: The study met its primary decision-making target with one major molecular response in BCR–ABL transcript levels. Overall, the data showed, in this clinical setting, the immunogenicity and safety of the vaccine.

Limitations: The study did not complete recruitment and there were multiple hurdles that contributed to this failure. This is disappointing given the robust induction immune responses against WT1 T-cell responses in 7 out of 10 evaluable patients.

Future work: Evaluation of the p.DOM–WT1 vaccines in AML remains attractive clinically, but it is unlikely to be feasible at this time. Combination of the DNA vaccine approach with strategies to expand T-cell responses with immunomodulatory antibodies is in development.

Funding details: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, and Bloodwise.
2050-4365
3
NIHR Journals Library
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Bowers, Megan
e76368dc-819f-4069-93f2-e1eee7bc691e
Hamid, Debbie
9e13568d-14a1-463f-8bd7-97e6bf02b62c
Maishman, Thomas
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Regan, Scott
36c7828e-82ce-4e33-87b3-f3cc04d351cb
Wood, Wendy
c7e12f30-5332-4717-a0c8-328775e06364
Cazaly, Angelica
944b91cc-ab19-463c-ad08-a6b04c6e628d
Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294
Ottensmeier, Christian
42b8a398-baac-4843-a3d6-056225675797
Bowers, Megan
e76368dc-819f-4069-93f2-e1eee7bc691e
Hamid, Debbie
9e13568d-14a1-463f-8bd7-97e6bf02b62c
Maishman, Thomas
cf4259a4-0eef-4975-9c9d-a2c3d594f989
Regan, Scott
36c7828e-82ce-4e33-87b3-f3cc04d351cb
Wood, Wendy
c7e12f30-5332-4717-a0c8-328775e06364
Cazaly, Angelica
944b91cc-ab19-463c-ad08-a6b04c6e628d
Stanton, Louise
8b827763-d839-4b4b-bbf2-358a84110294

Ottensmeier, Christian, Bowers, Megan, Hamid, Debbie, Maishman, Thomas, Regan, Scott, Wood, Wendy, Cazaly, Angelica and Stanton, Louise (2016) Wilms’ tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN) (Efficacy and Mechanism Evaluation, , (doi:10.3310/eme03030), 3, 3) Southampton, GB. NIHR Journals Library 110pp.

Record type: Monograph (Project Report)

Abstract

Background: In the UK almost 7000 people are diagnosed with leukaemia each year, but despite continuing advances in diagnosis and treatment with new drugs, such as the tyrosine kinase inhibitors, the majority of these patients will eventually die from their disease. Until quite recently, the only treatment to offer the possibility of long-term disease-free survival was allogeneic stem cell transplantation. However, this carries a substantial risk of mortality and is available to only a minority of patients.

Objectives: The aim of the study was to test the hypothesis that molecular and clinical responses, induced by T lymphocytes (T cells), can be predicted by increases in the number of CD8+ (cluster of differentiation 8-positive) T cells specific for the vaccine-encoded T-cell epitopes. This project also aimed to build on the established programme of deoxyribonucleic acid (DNA) fusion-gene vaccination delivered by intramuscular injection, exploiting a unique experience with electroporation, to induce durable immune responses with the aim of controlling disease by precision attack of the tumour by CD8+ T cells.

Method: A non-randomised, open-label, single-dose-level Phase II clinical trial in two patient groups [chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML)] on stable doses of imatinib. Human leucocyte antigen A2-positive (HLA A2+) patients were vaccinated with two DNA vaccines: (1) p.DOM–WT1-37 (epitope sequence: VLDFAPPGA); and (2) p.DOM–WT1-126 (epitope sequence: RMFPNAPYL). The HLA A2-negative patients formed an unvaccinated control group. The sample size for the HLA A2+ group was originally determined following Simon’s optimal Phase II trial design (Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1–10). This was changed to A’Hern’s single-stage design during the course of the trial (A’Hern RP. Sample size tables for single-stage phase II designs. Stat Med 2001;20:859–66), which was endorsed by the trial’s independent oversight committees.

Results: The study included 12 patients with CML who were vaccinated and nine patients with CML who were unvaccinated as the control group. Both the vaccines and the electroporation were safe, with no new or unexpected toxicities. The evaluation adverse events of special interest (heart, bone marrow, renal) did not reveal safety concerns. Two BCR–ABL (breakpoint cluster region–Abelson murine leukaemia viral oncogene homolog 1) responses were observed, both of which were defined as a major response, with one in each group. Two Wilms’ tumour antigen 1 (WT1) molecular responses were observed in the vaccinated group and one was observed in the control group. At an immunological level, the vaccine performed as expected.

Conclusions: The study met its primary decision-making target with one major molecular response in BCR–ABL transcript levels. Overall, the data showed, in this clinical setting, the immunogenicity and safety of the vaccine.

Limitations: The study did not complete recruitment and there were multiple hurdles that contributed to this failure. This is disappointing given the robust induction immune responses against WT1 T-cell responses in 7 out of 10 evaluable patients.

Future work: Evaluation of the p.DOM–WT1 vaccines in AML remains attractive clinically, but it is unlikely to be feasible at this time. Combination of the DNA vaccine approach with strategies to expand T-cell responses with immunomodulatory antibodies is in development.

Funding details: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, and Bloodwise.

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e-pub ahead of print date: 14 April 2016
Organisations: Faculty of Medicine, Clinical Trials Unit

Identifiers

Local EPrints ID: 392740
URI: https://eprints.soton.ac.uk/id/eprint/392740
ISSN: 2050-4365
PURE UUID: f1ce0001-b4a0-44d2-92af-47ad6c212d40
ORCID for Louise Stanton: ORCID iD orcid.org/0000-0001-8181-840X

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Date deposited: 18 Apr 2016 08:03
Last modified: 19 Jun 2019 00:34

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