The application for the release of CAR T cells for trial and sterility testing at Wellington SCL Clinical Laboratories at Wellington Hospital was lodged pursuant to section 34 of the Hazardous Substances and Novel Organisms Act (HSNO) 1996 ("HSNO Act"). At the very least, the co-stimulatory domain activates the cell-killing response of the T-CAR cell, via the CD3ζ (zeta) stimulatory domain as used in first-generation T-CAR cells (Fig. 2; Maus et al, 2014 ). First-generation T-CAR cells often provided limited or temporary cancer remissions, in part because of limited proliferation (often clinically referred to as expansion) of T-CAR cells in patients.
The co-stimulatory domains induce the cell-killing response of the T cell, and with later-generation CAR T cells, stimulate CAR T-cell proliferation and or the production of various cytokines (molecules that stimulate and attract other immune cells, increasing the immune response). The CAR name specifies its antigen recognition domain as well as its three co-stimulatory domains [CD19+CD28+Toll-like receptor 2+CD3ζ (zeta)].
Capacity of WZTL-002 CAR T-cells to cause adverse environmental effects
As WZTL-002 cells are an experimental therapy, the applicant declares that one of the exclusion criteria (under s30(3) of the Medicines Act 1981) for the study protocol is pregnancy. Therefore, the likelihood that WZTL-002 cells could have adverse effects on a fetus via receiving WZTL-002 cells during pregnancy is highly unlikely. To minimize this possibility, the applicant notes in the application that screening for residual LV-1928T2z lentiviral vector in WZTL-002 cultures will be performed at Wellington SCL laboratories as part of the study protocol under s30(3) of the Medicines Act.
WZTL-002 cell cultures in which residual LV-1928T2z lentiviral vector is detected will not be administered to patients in the study. Therefore, the likelihood that WZTL-002 cells could have adverse effects on another individual via the reversal of the lentiviral vector LV-1928T2z is highly unlikely. WZTL-002 cells are patient-derived blood cells, likely to be secreted only if the patient.
Therefore, we conclude that any adverse effects of transfer of WZTL-002 cells to an unintended subject via direct secretion is highly unlikely. As with any intravenously administered drug, there is the possibility that WZTL-002 cells could be inadvertently introduced into a person other than the intended recipient through mishandling (e.g. administration of WZTL-002 cells from the wrong patient). Another possible way for WZTL-002 cells to enter the environment is through improper disposal of the cells, either before or after their intended use.
The likelihood of WZTL-002 cells being inadvertently released into the environment is further reduced by the fact that WZTL-002 cells can only be administered by physicians.
Māori considerations
Even in the highly unlikely event of such an occurrence, an adverse effect on the health and safety of an unintended recipient is highly unlikely, due to the characteristics of autologous WZTL-002 cells, as described in the application and in this advisory document. Staff. As noted in paragraphs 28-32, the Wellington SCL testing facility is accredited by IANZ under the Testing Laboratory Registration Act 1972, to the ISO Standard (Wellington SCL 2015). In addition, Wellington SCL staff are highly trained, with extensive experience in the handling and disposal of potentially infectious human blood samples.
The study protocol of the ENABLE trial, under section 30(3) of the Medicines Act, requires Wellington SCL to remove the cells in a way that ensures their destruction. However, if WZTL-002 cells were to find their way into the environment, as blood cells, they would not survive long outside the host as stated in paragraph 15. Therefore, the likelihood of an adverse effect on the health and safety of the public or the environment is, or is very unlikely to establish an undesirable self-sustaining population.
APP203750 Release of CAR-T cells for clinical trial of certain blood cancers
Māori Perspectives Report (MPR)
Executive Summary
Purpose and scope of this MPR
Ngā here ture (Statutory obligations)
Section 6(d) of the Act obliges all persons exercising functions, powers and duties in terms of the Act, in order to achieve the purpose of the Act, to take into account the relationship of Māori and their culture and traditions to their ancestral lands, water, to take, sites, waahi tapu, valued flora and fauna, and other taonga. In accordance with section 8, the decision-maker is expected to take into account the principles of the Treaty of Waitangi (Te Tiriti o Waitangi).
Assessment of impacts on cultural receptors
Analysis of impact
Te Tiriti o Waitangi
Kupu whakatepe (Conclusion)
Impact on the relationship of Maori and their culture and traditions with their environment and taonga. This application is unlikely to significantly affect the relationship of Māori and their culture and traditions to their environment and taonga, including culturally significant species, resources and places and the customary values, practices and uses associated with those taonga. No problem arises because Māori participating in the trial can take Māori interests into account.
EPA is making an informed decision because of the Māori perspective presented in this report. EPA is acting reasonably and in good faith in considering the Māori perspective for the application. Finally, we also note that the applicant has submitted a detailed application of its proposed clinical trial to the Māori Research Advisory Group (RAG-M) of the Capital & Coast District Health Board (CCDHB).
We also note, in relation to the point about disposal of the cells in the above assessment, that the trial participants' cells cannot be returned to them due to health and safety regulations. In the RAG-M approval of the clinical trial, that the applicant intends to use a consent form enabling Māori participants in the ENABLE trial to specify a karakia to be recited upon disposal of any unused cells or tissue taken from the participant during the course of the study (appendix 1, section 2d).
Summary of information from other agencies
DOC responded that they believe the proposed release of WZTL-002 cells has no implications for biodiversity and that they have no objection to approving the application.
Legislative criteria to be considered
Assessment of the risk of WZTL-002 cells conditional release against legislative criteria
Screening of WZTL-002 cells for sterility/safety testing will be performed at Wellington SCL, an IANZ accredited testing facility, as a contractor under a license issued by Medsafe to manufacture WZTL-002 cells. WZTL-002 cells will be handled and disposed of by trained medical personnel in accordance with accepted medical practices as a drug used in a clinical trial for specific patients. The use of WZTL-002 cells in a phase 1 clinical trial in New Zealand is unlikely to significantly impact the relationship of Māori and their culture and traditions with them.
WZTL-002 cells will not be administered to pregnant women, as a study protocol exclusion criterion under section s30(3) of the Medicines Act. WZTL-002 cells will not be administered to HIV-positive patients as an exclusion criterion from the study protocol under section s30(3) of the Medicines Act. WZTL-002 cells cannot survive for long periods of time outside of a host organism without human intervention.
WZTL-002 cells are easily destroyed by heat, drying, ultraviolet light, bleach, household disinfectants, and detergents. If the applicant receives approval from the EPA to release the WZTL-002 cells, it must submit an application to Medsafe to use the cells in a Phase 1 clinical trial at Wellington Hospital. According to section 30 of the Medicines Act 1981, the clinical trial cannot proceed until approval is given by the Director General of the Ministry of Health (Ministry of Health 2018b).
We recognize that all doctors who administer vaccines in New Zealand are expected to do so in accordance with the standards set out in the Ministry of Health's Guide to the Regulation of Therapeutic Products in New Zealand Part 11 (Ministry of Health 2018b), which specifies requirements for regulatory approval and good clinical practice in clinical trials.
Proposed controls
New Zealand Blood Service's screening procedures prevent blood donation from patients who have ever had leukemia and/or lymphoma. Therefore, we consider that the imposition of the controls proposed by the applicant under this application would be redundant to those of the clinical trial approval issued by Medsafe (if granted) and/or the WZTL-002 Cell Manufacturing License. We consider that the primary risk of this testing from an environmental perspective is that.
We consider that what little risk remains regarding the inadvertent creation of an RCL is addressed either in the applicant's existing development approval (APP203214) for the creation of the LV-1928T2z vector, and/or the Manufacturing License issued by the applicant from Medsafe Cells WZTL-002 (discussed in paragraphs 30 and 69). Notwithstanding the above, and although we consider it highly unlikely that any adverse environmental effects would occur from the release of WZTL-002 cells, we consider it appropriate to place some controls on the application due to the experimental nature of the therapy. Our proposed controls (detailed in paragraph 79) specify notification requirements for both trial initiation and termination, limitations on cell release points, and a limitation on the duration of EPA approval, if granted.
International obligations
As described in Sections 21–26, third-generation lentiviral vector systems are extremely safe, and an RCL has never been detected in the more than 25 years of their use.
Conclusion and recommendation
We note, and the Malaghan Institute for Medical Research acknowledges, that an approval of a qualifying drug granted under section 38I of the HSNO Act is not an approval to use that drug until it has been lawfully supplied for use under Medicines Act 1981.
[ PubMed ] Neelapu S. S., Locke F. L., Bartlett N. L., Lekakis L. J., Miklos D. B., Jacobson C. A., Braunschweig I, Oluwole O. O., Siddiqi T, Lin [ PubMed ] Schuster S. J., Svoboda J., Chong E. A., Nasta S. D., Mato A. R., Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D kadagiti droga.
[ PMC gratis artikel ] [ PubMed ] Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD.
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