1

EPA Staff Assessment Report on application APP203750

To release genetically modified live Chimaeric Antigen

Receptor T-cells for use in a Phase 1 dose escalation clinical

trial to examine safety and efficacy in patients with relapsed and

refractory B-cell lymphomas.

20 September 2019

Application number: APP203750

Purpose:

To release genetically modified live Chimaeric Antigen

Receptor T-cells for use in a Phase 1 dose escalation

clinical trial to examine safety and efficacy in patients

with relapsed and refractory B-cell lymphomas.

Applicant: The Malaghan Institute for Medical Research

Application Lead:

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ADVICE TO THE DECISION MAKER

Executive summary and recommendation

On 16 September 2019, the Environmental Protection Authority (EPA) formally received an application

from the Malaghan Institute for Medical Research (the applicant) to release genetically modified

organisms from containment. The organisms, live Chimaeric Antigen Receptor T-cells (CAR T-cells)

are intended for the treatment of patients with relapsed and refractory B-cell lymphomas in a Phase 1

dose escalation clinical trial at Wellington Hospital. The application to release the CAR T-cells for the

trial and for sterility testing in the Wellington SCL clinical laboratories at Wellington Hospital was

lodged pursuant to section 34 of the Hazardous Substances and New Organisms (HSNO) Act 1996

(the “HSNO Act”).

Section 38I of the HSNO Act provides for a rapid assessment of applications received under section

34, if the application seeks the release of a qualifying organism. A qualifying organism is, in part, a

new organism (including a genetically modified organism) that is a medicine or is contained in a

medicine.

Based on the information in the application and from other published sources, we found, based on:

the known safety profiles of CAR T-cell therapies to date

an existing development approval for CAR T-cells from EPA

an existing licence to manufacture CAR T-cells from Medsafe

the IANZ accreditation of Wellington SCL

the experience of Wellington Hospital staff in the safe handling and disposal of medical

samples and waste

the lack of adverse effect on Māori relationships with their environment and taonga,

that it is highly improbable that CAR T-cells could form a self-sustaining population and have

significant adverse effects on the health of the public, any valued species, natural habitats, or the

environment.

Therefore, we recommend that the application is approved, subject to the proposed controls.

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Table of Contents

Executive summary and recommendation ......................................................................................... 2

Table of Contents .................................................................................................................................. 3

Purpose of this document .................................................................................................................... 4

Application summary ............................................................................................................................ 4

B-cell non-Hodgkin’s lymphoma ......................................................................................................... 4

Chimaeric antigen receptor T-cells – history and effectiveness ...................................................... 5

The organism: autologous WZTL-002 human CAR T-cells ............................................................... 8

Māori considerations .......................................................................................................................... 13

Summary of information from other agencies ................................................................................. 17

Legislative criteria to be considered ................................................................................................. 18

Proposed controls ............................................................................................................................... 19

International obligations ..................................................................................................................... 20

Conclusion and recommendation ..................................................................................................... 20

References ........................................................................................................................................... 22

Appendix 1: Endorsement of WZTL-002 clinical trial by the Research Advisory Group-Māori of

the Capital & Coast District Health Board ......................................................................................... 24

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Purpose of this document 1. This Staff Assessment Report was prepared by the Environmental Protection Authority’s (EPA)

staff to assist the decision-maker in considering application APP203750. It contains information

from the applicant and other readily available sources, and it sets out the statutory criteria

applicable to the consideration of this application under the HSNO Act.

Application summary 2. On 16 September 2019, The Environmental Protection Authority formally received an application

from the Malaghan Institute for Medical Research (MIMR) seeking approval to release genetically

modified live WZTL-002 cells under section 34 of the Hazardous Substances and New Organisms

(HSNO) Act 1996. WZTL-002 cells are autologous (ie, patient-derived) Chimaeric Antigen

Receptor T-cells (CAR T-cells) that will be developed under an existing containment approval

(APP203214). If approved for release, WZTL-002 cells are intended for use in the treatment of

patients with relapsed and refractory B-cell non-Hodgkin’s lymphomas in a Phase 1 dose

escalation clinical trial (the ENABLE trial) and for sterility testing in a clinical laboratory. The

application was lodged pursuant to section 34 of the HSNO Act.

B-cell non-Hodgkin’s lymphoma 3. Lymphomas are cancers that start in the bone marrow, in differentiating stem cells that are

destined to become lymphocytes, that is, immune cells, such as T-cells and B-cells (American

Cancer Society 2019a). Non-Hodgkin’s lymphoma (NHL) is a general descriptor for more than 50

different B-cell cancers (Swerdlow et al, 2016), including diffuse large B-cell lymphoma, the most

common type of B-cell NHL (Armitage et al, 2017).

4. There were 923 new registrations of NHL in New Zealand in 2017, which makes it among the 10

most prevalent cancers in the country (Ministry of Health 2018a). There were 317 NHL deaths in

2013, the most recent year from which data are available (Ministry of Health 2016). The disease is

approximately 35% more prevalent among men than women (Ministry of Health 2018a). Māori

have essentially equal incidences of NHL per 100,000 population as non-Māori (Ministry of Health

2019). The Ministry of Health does not distinguish between T-cell and B-cell NHL in its statistics,

so it is not clear what proportion of these registrations and deaths were the result of B-cell NHL.

5. Despite an increasing incidence of lymphomas in New Zealand (and around the world), the

prognosis for patients is generally improving, with decreasing death rates observed between 1995

(5.0 per 100,000) and 2009 (4.7 per 100,000). Death rates among Māori are somewhat higher

than among non-Māori at 5.2 deaths per 100,000 (National Lymphoma Tumour Standards

Working Group 2013).

Current Non-Hodgkin’s lymphoma treatments in New Zealand 6. Current standards of care outline the recommended treatments to be made available to all

lymphoma sufferers in New Zealand (National Lymphoma Tumour Standards Working Group

2013). These include various types of chemotherapy regimens, including both small molecules

and monoclonal antibodies, often in combination (Armitage et al, 2017), radiation therapy,

surgery, stem cell transplantation, and finally, palliative care when other treatment options have

failed (National Lymphoma Tumour Standards Working Group 2013). Treatment options vary

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widely, depending on the type of B-cell lymphoma being treated (American Cancer Society

2019b).

7. Although there are lymphoma and leukaemia patients currently residing in New Zealand who have

received some form of CAR T-cell therapy (see application), no CAR T-cell therapy of any kind is

currently available within New Zealand. Because CAR T-cells are human cells that carry a foreign

gene, they are considered to be genetically modified organisms under the HSNO Act. Therefore,

CAR T-cells are classified as new organisms under the HSNO Act, and any CAR T-cell therapy,

including the one described in the application, requires an approval for the release of a new

organism from EPA. This application, if approved, would provide new treatment options for eligible

patients in New Zealand in the Malaghan Institute’s ENABLE trial.

8. As discussed in the next section of this staff advice, most CAR T-cell therapies are still

experimental and are being assessed in a large number of clinical trials. As such, they are

generally only being used in individuals for whom other treatment options have failed. Even CAR

T-cell therapies approved by the Food and Drug Administration (FDA) in the United States are

only for use in patients for whom other treatment options have failed (generally referred to as

relapsed and refractory lymphomas and leukaemias). Consistent with worldwide best practice, the

ENABLE trial is only for patients that suffer from relapsed and refractory NHL, as noted in the

application.

Chimaeric antigen receptor T-cells – history and effectiveness 9. Cancer cells undergo many mutations relative to the normal cells in the body that would normally

lead to their destruction by the immune system (Muenst et al, 2016). Although such

immunosurveillance normally protects humans and other vertebrates from cancer, evasion of the

immune system that results in malignancies can occur by a wide variety of mechanisms (Muenst

et al, 2016). Thus, a great deal of clinical research involves exploring ways to overcome this

immune system evasion and re-engage immunosurveillance mechanisms in the destruction of

tumours (Maus et al, 2014; Muenst et al, 2016; ClinicalTrials.gov 2019c; Weinkove et al, 2019).

Such immune system approaches to cancer treatment are collectively known as immunotherapy.

10. One such promising line of immunotherapy research involves genetic modification of a specific

type of immune cell, called a T-cell, with a gene encoding a protein that will directly recognise and

kill tumour cells, called a chimaeric antigen receptor (CAR). The genetically modified T-cells are

known as CAR T-cells, and since they were first conceived and developed in the late 1980s

(Gross et al, 1989), a wide variety of CARs have been trialled. Their clinical effectiveness was

demonstrated for the first time in 2012 (Rosenbaum 2017).

11. Ordinarily, T-cell responses involve a complex series of steps involving recognition of a foreign

entity (such as an infecting bacterium or an immunosurveilled cancer cell), killing the cell, and

processing the killed cell in such a way that antigens (generally short processed parts of proteins

from the infecting entity) are displayed to T-cells in conjunction with the Major Histocompatibility

Complex (MHC; a group of proteins used by the immune system to distinguish ‘self’ from ‘non-

self’) by so-called antigen presenting cells (APCs; Fig. 1). The antigen is recognised by T-cell

receptors (TCRs) on a subset of T-cells in the body, in conjunction with co-stimulating signals

from the APC recognised by the CD28 receptor, which activates the intracellular signalling domain

or domains (also called co-stimulation domains) on the receptors. Activation of the co-stimulation

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domains signals the T-cell to activate its cell-killing functions, as well as to divide and proliferate

and recruit other immune cells to attack the invading organism (Fig. 1; Weinkove et al, 2019).

12. The idea behind CAR T-cell therapy is to bypass the normal mode of T-cell stimulation and equip

the T-cell with a receptor that allows the T-cell to directly kill cells carrying the CAR’s target

antigen (ie, tumour cells; Fig. 1), which bypasses the need for APCs, as well as many

mechanisms by which tumours evade immunosurveillance (Maus et al, 2014; Weinkove et al,

2019). Conceptually, CAR T-cells are relatively simple, as they are a specific type of immune cell

(the T-cell) that is genetically modified with a single gene construct, called a chimaeric antigen

receptor (CAR; Fig. 1, Fig. 2). Upon binding of the tumour cell antigen, the T-cell is directly

activated via one or more co-stimulation domains in the CAR (Fig. 1, Fig. 2) to kill the tumour cell,

as well as to divide and proliferate to attack other tumour cells.

13. CARs have a four segment structure consisting of 1) an extracellular antigen recognition domain,

2) a so-called hinge domain, 3) a transmembrane (ie, membrane-spanning) domain, and 4) one or

more intracellular signalling domains (Fig. 2). At a minimum, the co-stimulation domain activates

the cell killing response of the CAR T-cell, via the CD3ζ (zeta) stimulation domain as were used in

first generation CAR T-cells (Fig. 2; Maus et al, 2014).

14. First generation CAR T-cells often provided limited or temporary remissions of cancers, in part

because of limited proliferation (often referred to clinically as expansion) of the CAR T-cells in

patients. Therefore, additional co-stimulation domains were added to later generation CARs (Fig.

Figure 1. T-cell activation in wild-type and genetically modified CAR T-cells. (adapted from Weinkove et al, 2019). (a) a peptide antigen from a killed foreign or cancer cell is displayed in conjunction with a Major Histocompatibility Complex (MHC) cell surface protein by an antigen-presenting cell (APC), and is recognised by the T-cell receptor (TCR) in a subpopulation of

T-cells in the body. This recognition and antigen binding activates the T-cell’s cell-killing functions. Optimal activation and expansion of the T-cell population is dependent in part on co-stimulation via the CD28 receptor, which activates a separate stimulatory signal to the T-cell via recognition of CD80 or CD86 domains on the APC. (b) an antigen on a cell surface molecule of a tumour cell is recognised by an antigen recognition domain on a CAR, which directly activates the cell-killing functions of the T-cell as well as proliferation responses via multiple co-stimulation domains in the engineered CAR.

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1, Fig. 2) in attempts to aid in the T-cell’s ability to kill target cells, as well as the antigen

recognition-driven expansion of the CAR T-cell population, thus amplifying the anti-cancer

response (Maus et al, 2014; Weinkove et al, 2019). Stronger T-cell expansion responses may

enable the use of lower initial numbers of CAR T-cells, which is thought to lessen cytokine release

syndrome (a known adverse effect on the CAR T-cell recipient resulting from the killing of large

numbers of cancer cells; see paragraph 36) responses in recipients of the therapy (Lai et al, 2017;

Weinkove et al, 2019), see also paragraphs 36 and 48.

15. CAR T-cell therapies have proven sufficiently effective that the FDA approved two second-

generation CAR T-cell therapies in 2017: tisagenlecleucel (Kymriah™), for advanced leukaemia in

children and adults, and axicabtagene ciloleucel (Yescarta™) for the treatment of several

relapsed and refractory large B-cell lymphomas (see application section 2.3, p. 7; NCI Staff 2017).

16. Despite showing great strides in improved patient outcomes, current CAR T-cell therapies are not

completely effective, and many patients’ cancers return, despite initial remission even with third

generation CARs. CAR T-cells are still essentially bespoke and experimental therapies, and many

aspects of their function and action are still not well understood (Maus et al, 2014; Weinkove et al,

2019). Thus, research continues into improving and broadening the effectiveness of CAR T-cells

for a wider range of cancer sufferers, and there are currently 506 CAR T-cell clinical trials around

the world that are listed as active and/or recruiting on the US National Library of Medicine’s

Clinical Trials.gov website (ClinicalTrials.gov 2019c).

Figure 2. First, second, and third-generation Chimaeric Antigen Receptors (CARs). (adapted from Maus et al, 2014). scFv: antibody single-chain variable fragment, which specifically recognises and binds a cell surface protein found on cancer cells; hinge: a “linker” region between the scFv and the transmembrane domain; transmembrane domain: a segment of hydrophobic (having poor water-solubility) amino acids that span the hydrophobic cellular membrane barrier; costimulation domain(s): one or more protein-binding domains derived from other immune cell receptor proteins that transduce a signal upon scFv binding of the cancer cell. The co-stimulation domains trigger the cell-killing response of the T-cell, and with later generation CAR T-cells, stimulate CAR T-cell proliferation, and or production of various cytokines (molecules that stimulate and attract other immune cells, enhancing the immune response).

Transmembrane domain

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The organism: autologous WZTL-002 human CAR T-cells 17. WZTL-002 CAR T-cells (referred to hereafter as WZTL-002 cells) are autologous (ie, patient-

derived) third generation CAR T-cells genetically modified with the CAR 1928T2z. The name of

the CAR specifies its antigen recognition domain, as well as its three co-stimulation domains

[CD19+CD28+Toll-like Receptor 2+CD3ζ (zeta)]. The CAR antigen recognition domain is derived

from the short-chain variable fragment (scFv) of an antibody against the human B-cell surface

marker CD19 (see application section 2.3). This antigen recognition domain recognises and binds

to any human B-cell, and this binding activates the intracellular co-stimulation domains to activate

the CAR T-cell to directly kill the B-cell (Maus et al, 2014; Weinkove et al, 2019) .

18. Like other anti-CD19 CAR T-cell therapies, WZTL-002 cells can kill healthy B-cells in addition to

cancerous B-cells. This can result in an immune deficiency syndrome known as

hypogammaglobulinaemia. Immunoglobulin infusions are generally given to patients exhibiting

this condition, which are readily available in New Zealand (see application section 3.0, p.13).

19. As a third generation CAR, 1928T2z has three intracellular T-cell signalling domains: CD28, Toll-

like-receptor 2 (TLR2), and CD3ζ (see application). A key feature of the CAR used in WZTL-002

cells that distinguishes it from most other CAR T-cell therapies to date is the TLR2 domain, which

is currently being tested for its efficacy in patients based on its stimulation of cytokine production

and T-cell expansion (Lai et al, 2017; Weng et al, 2018).

20. An earlier CAR, called 1928zT2 (differing from 1928T2z in the relative position of the CD3ζ and

TLR2 domains in the CAR) is currently being used in CAR T-cell clinical trials in patients with

relapsed B-cell acute lymphoblastic leukaemia (B-ALL; Lai et al, 2017; Weng et al, 2018). Strong

CAR T-cell expansion and complete B-ALL remission were reported in an early study (Lai et al,

2017), and complete remission against relapsed and refractory extramedullary B-ALL (ie

leukaemia in tissues outside the bone marrow) were reported in a subsequent, still ongoing,

clinical trial (Weng et al, 2018; ClinicalTrials.gov 2019a).

Manufacture, quality assurance and quality control of WZTL-002 CAR T-cells

Safety of lentiviral vectors

21. The WZTL-002 cells are manufactured at the applicant’s PC2 containment facility under an EPA

approval (application APP203214), and a licence to manufacture vaccines and sera from Medsafe

(Medsafe 2019b), using a replication-incompetent lentiviral vector that has been verified to lack

any revertant replication-competent lentiviral particles (RCLs). It is important to note that, due to

the safety features incorporated into lentiviral vector systems, there has never been a RCL

detected in the entire history of use of lentiviral vectors spanning more than 25 years of human

clinical trial work (Morgan & Boyerinas 2016; Cornetta et al, 2018a).

22. To elaborate on this point in the context of the manufacture and potential release of WZTL-002

cells, recombination could theoretically occur between the viral vector construct and the vector

packaging constructs. Such a recombined vector could theoretically infect another person via

transmission from a WZTL-002 cell recipient (Schambach et al, 2013). Such events have been

observed in the production of retroviral (ie, non-lentiviral) vectors, such as Moloney Murine

Leukaemia Virus (MLV) vectors (Cornetta et al, 2018b). To prevent such an occurrence using

lentiviral vectors, packaging is carried out in cells that carry the necessary replication and

packaging genes on separate plasmids. This decreases the probability of the re-creation of a RCL

because multiple independent recombination events would be required for this to occur. In the

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case of third generation lentiviral vectors, the packaging cells carry the requisite genes on three or

four separate plasmids (Schambach et al, 2013). In the case of the packaging system used in

APP203214, three separate plasmids are used (APP203750 application form, section 3.0, p 10).

23. An additional safety feature of the lentiviral vector production system used in APP203214 is that

packaging is carried out via transient transfection of the cells used in production (APP203214

application form, section 3.0, p 10). Therefore, the plasmids used in lentiviral vector production do

not replicate, and are only functional in the cells for protein production for a short time, limiting the

amount of time in which recombination may take place (Cornetta et al, 2018a).

24. Finally, third generation lentiviral vectors have precisely edited sequences that prevent the

translation of truncated viral vector proteins in regions of the vector that have some sequence

similarity, and therefore, the potential to recombine with viral sequences (Schambach et al, 2013).

The combination of multiple and redundant safety features into third generation lentiviral vectors

has rendered them so reliable that a recombination leading to a RCL has never been detected,

even in experimental systems designed to detect such low-frequency recombination events

(Schambach et al, 2013; Cornetta et al, 2018a).

25. Lentiviral vector safety was recently further confirmed through an extensive screening study of

nearly two dozen different T-cell products, after T-cell amplification in culture (Cornetta et al,

2018a). All the screened products were unsurprisingly negative for RCLs, since screening for

RCLs after production was also negative. These findings prompted the authors to suggest that the

requirement for screening for RCVs after T-cell amplification in approved trials in the United

States should be dropped if the vector product is found to be negative for RCL (Cornetta et al,

2018a).

26. Regardless of these findings and the unblemished safety record of lentiviral vectors, the applicant

states that they intend to test patient-derived CAR T-cells for replication-competent lentivirus in

containment at an external containment facility (Diatranz Otsuka) under its current development

approval APP203214 before their release to lymphoma patients (see application,section 3.0 p.

11).

Safety testing of WZTL-002 cells and culture supernatants

27. Clinical trials in New Zealand are expected by the Ministry of Health to comply with the European

Medicines Agency’s Guideline for good clinical practice E6 (European Medicines Agency 2016),

with certain modifications to ensure compliance with the Medicines Act 1981 (Ministry of Health

2018b). Under its Medsafe Licence to Manufacture approval (Medsafe 2019b), prior to their use

as a lymphoma treatment in patients in the ENABLE trial, the WZTL-002 cells must undergo

safety testing to ensure that the cultures are sterile (ie, they contain no biological contamination

such as bacteria or mycoplasmas), as well as to ensure that there is no residual replication-

defective LV-1928T2z viral vector.

28. To ensure compliance with these conditions, the applicant is applying to release the cells or cell

supernatants (ie, the liquid portion of the culture after the bulk of the WZTL-002 cells have been

separated by centrifugation) to a medical testing laboratory, specifically Wellington SCL, located

on-site at Wellington Hospital.

29. Under the HSNO Act, transfer of genetically modified organisms in containment requires transfer

to an MPI-approved containment or transitional facility that can comply with the controls imposed

on the relevant approval. However, because they generally conduct testing on human clinical

samples only, medical testing laboratories are not generally classified or certified as transitional or

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containment facilities under the Biosecurity Act 1993. Therefore, in order to carry out the

appropriate testing under its Licence to Manufacture WZTL-002 cells from Medsafe, MIMR

requires a release approval of the GMOs to Wellington SCL.

30. Medsafe has extensive requirements that it imposes on recipients of Licences to Manufacture

under the New Zealand Code of Good Manufacturing Practice (Medsafe 2019a), including:

a quality agreement detailing the responsibilities of the licence holder and the testing facility,

including disposal/destruction of the samples

assessment and approval of all contractors and suppliers

the traceability of all samples sent to the testing facility

secure containment of samples, including ensuring they are not contaminated or degraded in

transport

Thus, Wellington SCL’s testing activities are regulated by Medsafe under the Malaghan Institute’s

Medsafe-issued licence to manufacture CAR T-cells.

31. Moreover, Wellington SCL is accredited under the Testing Laboratory Registration Act 1972 by

the Crown entity International Accreditation New Zealand (IANZ; https://www.ianz.govt.nz/), to the

ISO 15189:2012 Standard (Wellington SCL 2015).

32. Based on its audits of the Malaghan Institute, Medsafe recommends that Malaghan’s Licence to

Manufacture should be renewed (Medsafe, personal communication), which would include

existing contractors, such as Wellington SCL.

Intended use and benefits of WZTL-002 CAR T-cells

33. The applicant states that they intend to administer WZTL-002 cells intravenously to patients with

relapsed and refractory B-cell non-Hodgkin lymphomas (a type of B-cell cancer) who are enrolled

in a Phase 1 dose escalation clinical trial. The purpose of a dose escalation trial is to assess both

the toxicity to the patient at a particular dose of the medicine being trialled, as well as effective

dosages of the medicine on the disease being treated (Office of New Drugs in the Center for Drug

Evaluation and Research 2013).

34. Data from previous clinical trials with second generation CAR T-cell therapies such as

tisagenlecleucel (CTL019; CART19; Kymriah™; ClinicalTrials.gov 2019b), or axicabtagene

ciloleucel (Yescarta™), reveal long-term remission in more than 50% of lymphoma patients

(Neelapu et al, 2017; Schuster et al, 2017). Although the WZTL-002 clinical trial is a Phase 1 trial

laboratory studies on the selectivity and effectiveness of WZTL-002 cells in vitro show that they

selectively kill cells that have the CD19 cell surface protein, because they only kill B-cells and not

cells that do not have the CD19 protein (see application, p. 13, and Figs. 2 and 3 therein). As

such, the potential immediate benefits of WZTL-002 cells to the lymphoma patients recruited to

the applicant’s Phase 1 dose escalation clinical trial include alleviation of lymphoma symptoms

and improved quality of life, cancer remission and prolonged survival.

35. WZTL-002 cells also have the potential to benefit the wider New Zealand community with non-

Hodgkin’s lymphoma, subject to positive results from the Phase 1 clinical trial described and

regulatory approval for commercial release.

Potential adverse effects from the use of WZTL-002 CAR T-cells

36. Treatment of various B-cell cancers with CAR T-cells is well known to cause a wide variety of

toxic effects in patients (Brudno & Kochenderfer 2016). Primary among these is the patient

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response commonly known as cytokine release syndrome (Brudno & Kochenderfer 2016), which

is a generalised inflammatory reaction caused by the release of large quantities of polypeptides

and small proteins collectively called cytokines that stimulate or modulate the immune system.

Reversible toxicities to the brain, liver, blood, heart, circulatory system, lungs, kidneys, digestive

system, and muscles have all been documented and studied in clinical trials (Brudno &

Kochenderfer 2016).

37. Under section 38I(4)(a) of the HSNO Act, in determining whether a qualifying organism is or is

contained in a qualifying medicine, the effects on the individual receiving it are not to be taken into

account. Therefore, an environmental risk assessment carried out under s38I must only take

potential adverse environmental effects, including the health and safety of the public, into account.

However, potential adverse effects in the patient must be considered in the context of the

potential for the qualifying organism to spread from the patient to clinicians, or members of the

general public, as we address below.

Capacity of WZTL-002 CAR T-cells to cause adverse environmental effects

38. In order for any potential adverse environmental effects from the use of WZTL-002 cells to occur,

the cells would first need to be transmitted in some way from the recipient to the environment.

There are a number of ways in which such an event might occur. These include:

transmission via blood donation after receiving WZTL-002 cells

adverse effects on a foetus during pregnancy after receiving WZTL-002 cells

reversion of the LV-1928T2z lentiviral vector to replication competence via recombination

direct shedding by WZTL-002 cell recipients

unintentional release of WZTL-002 cells via improper handling of the cells

Each of these potential pathways is discussed in turn below.

Transmission of WZTL-002 CAR T-cells via blood donation after treatment

39. Autologous T-cells such as WZTL-002 cells are expected to proliferate in patients after they are

administered in a clinical trial. While it is unlikely that a person who is seriously ill with non-

Hodgkin lymphoma will be inclined to donate blood, the possibility exists that autologous WZTL-

002 cells could potentially be transmitted from a recipient to another person via a transfusion of

blood donated by recipients after receiving treatment, particularly in the event that their cancer

goes into remission.

40. Because of the trial nature of the administration of CAR T-cells to cancer patients, the possibility

exists that a patient in the clinical trial could transmit some non-Hodgkin lymphoma cells to a

blood recipient in addition to the WZTL-002 cells. For this reason, the applicant states that CAR

T-cell recipients will be instructed that they must never donate blood for the rest of their lives.

41. Additionally, the New Zealand Blood Service has long-standing published eligibility criteria and

pre-donation screening procedures for blood donation in New Zealand (NZBlood 2019a, b),

including the completion of a donor health questionnaire which includes the potential donor’s

medical history (NZBlood 2019a). The Blood Service requires that people who have had

leukaemia or lymphoma are not eligible to donate blood (NZBlood 2019b). Therefore, the

likelihood that WZTL-002 cells could cause adverse effects on another person via a blood

transfusion is highly improbable.

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Transmission of WZTL-002 CAR T-cells to a foetus during pregnancy

42. In addition to blood donation by patients who have received WZTL-002 cells, another potential

route of transmission of WZTL-002 cells is to a foetus by treatment of a pregnant woman. Non-

Hodgkin’s lymphoma is often successfully treated and/or managed using existing conventional

treatments during pregnancy (Gurevich - Shapiro & Avivi 2019). Given that WZTL-002 cells are an

experimental therapy, the applicant states that one of its exclusion criteria (under s30(3) of the

Medicines Act 1981) for the study protocol is pregnancy.

43. Therefore, the likelihood that WZTL-002 cells could have adverse effects on a foetus via receiving

WZTL-002 cells during pregnancy is highly improbable.

Reversion of the LV-1928T2z lentiviral vector to replication competence

44. As noted in paragraphs 21-26, a reversion of a replication-incompetent lentiviral vector to

replication competence has never been observed, even in experiments designed specifically to

detect such an event. Regardless, it remains theoretically possible that reversion to replication

competence could occur in the course of the ENABLE trial, if approved, particularly if a patient is

HIV-positive.

45. To minimise this possibility, the applicant notes in the application that screening for residual

LV-1928T2z lentiviral vector in WZTL-002 cultures will be carried out at Wellington SCL

laboratories as part of its 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.

46. Furthermore, the applicant states that candidates for the ENABLE trial will be screened for HIV-

positive status in pre-trial blood tests.

47. HIV-positive status amongst candidate ENABLE trial participants is one of the trial’s exclusion

criteria (as specified under s30(3) of the Medicines Act 1981).

48. Therefore, the likelihood that WZTL-002 cells could have adverse effects on another person via

the reversion of the LV-1928T2z lentiviral vector is highly improbable.

Direct shedding of WZTL-002 CAR T-cells by recipients

49. Although rare, haemorrhaging in CAR T-cell recipients has been observed as one of a range of

symptoms of cytokine release syndrome (Maude et al, 2014; Brudno & Kochenderfer 2016). Such

events are usually managed by providing the patient with treatments to ensure blood clotting,

together with other treatments to manage the cytokine release syndrome (Maude et al, 2014;

Brudno & Kochenderfer 2016).

50. WZTL-002 cells are patient-derived blood cells, which will only likely be shed if the patient

receives a cut, WZTL-002 cells will only be shed very rarely and in extremely small quantities from

treated patients. WZTl-002 cells can survive only for a very short period of time outside the

patient, and can easily be destroyed with simple household cleaning solutions. Therefore, we

conclude that any adverse effects of transmission of WZTL-002 cells to an unintended person via

direct shedding is highly improbable.

Unintentional release of WZTL-002 CAR T-cells by improper handling of the cells

51. As with any intravenously administered medicine, there is a possibility that WZTL-002 cells could

accidentally be introduced into a person other than the intended recipient through mishandling

(eg, administering WZTL-002 cells derived from the wrong patient). Such an event is rendered

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unlikely by the fact that WZTL-002 cells will only be administered by medical professionals who

are trained in the handling and intravenous administration of medicines, including cross-

referencing medicine and patient records, as well as the proper disposal and destruction of

medical waste, as set out in the ENABLE trial’s study protocol, as required under s30(3) of the

Medicines Act. Even in the highly unlikely event of such an occurrence, an adverse effect on the

health and safety of an unintended recipient is highly improbable, due to the characteristics of

autologous WZTL-002 cells, as described in the application, and this Staff advice document.

52. Another possible means by which WZTL-002 cells could find their way into the environment is via

improper disposal of the cells, either before or after its intended use. 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 15189:2012 Standard (Wellington SCL 2015). Additionally,

Wellington SCL staff are highly trained, with extensive experience in the handling and disposal of

potentially infectious human blood samples. The ENABLE trial’s study protocol, in accordance

with s30(3) of the Medicines Act, specifies that Wellington SCL must dispose of the cells in a way

that ensures that they are killed.

53. The likelihood that WZTL-002 cells might be unintentionally released into the environment is

further mitigated by the fact that WZTL-002 cells can only be administered by medical

professionals, who are trained in the proper disposal of medicines and medical waste products.

Regardless of this, were WZTL-002 cells to find their way into the environment, as blood cells,

they would not survive long outside a host, as noted in paragraph 15.

54. Therefore, the likelihood of an adverse effect on the health and safety of the public or the

environment occurring, or an undesirable self-sustaining population establishing is highly

improbable.

Māori considerations 55. As specified in Part 2 of the HSNO Act (Purpose of Act), the EPA must recognise and account for

(among other things) several principles and matters of relevance to Māori, particularly as they

relate to:

the maintenance and enhancement of the capacity of people and communities to provide for

their own economic, social, and cultural well-being and for the reasonably foreseeable needs

of future generations (section 5(b))

the relationship of Māori and their culture and traditions with the ancestral lands, water, sites,

wāhi tapu, valued flora and fauna, and other taonga (section 6(d))

the principles of the Treaty of Waitangi (Te Tiriti o Waitangi) (section 8)

56. The assessment of these principles and matters of relevance to Māori was undertaken by the

EPA’s Māori advisory Policy and Operations group, Kaupapa Kura Taiao. The full text of this

assessment is reproduced below.

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APP203750 Release of CAR-T cells for clinical trial of certain blood cancers

Māori Perspectives Report (MPR)

for Non-Notified, Release of a Qualifying Organism Application

Executive Summary

Kaupapa Kura Taiao (the EPA’s Māori Policy and Operations team) has undertaken an assessment to

consider potential impacts of the release and transfer of Chimeric Antigen Receptor (CAR) T-Cells for

use in an investigator led Phase 1 Clinical trial to treat patients with relapsed and refractory B-Cell

Lymphomas, on the economic, social, and cultural well-being of Māori, and the relationship of Māori

with the environment, pursuant to sections 5(b), 6(d) and 8 of the HSNO Act.

The use of the CAR T-Cells, in accordance with the details provided in the application, is not likely to

significantly affect the relationship of Māori and their culture and traditions with their environment and

taonga, including culturally significant species, resources, and places, and the customary values,

practices and uses associated with these taonga. However, the participants that are Māori should

have the opportunity to dispose of their cells in accordance with their tikanga.

The use of the CAR T-Cells, in accordance with the details provided in the application, is not likely to

affect the ability and capacity of Māori to maintain their economic, social, and cultural well-being.

Ngā Mātāpono o Te Tiriti o Waitangi (the Principles of the Treaty of Waitangi) have been considered in

relation to this application – no issues arise in this regard.

Purpose and scope of this MPR

The purpose of this MPR is to inform the decision maker on the potential impacts on the relationship of

Māori and their culture and traditions with their environment and taonga, and any issues that arise

under the principles of The Treaty of Waitangi (Te Tiriti o Waitangi) from the application for the release

of CAR-T cells for clinical trial of certain blood cancers. The MPR also provides advice to the decision

maker on any potential impact on the capacity of Māori to maintain and enhance economic, social and

cultural wellbeing.

The MPR is an assessment under s 6(d) and 8 of the Act. Advice is also provided on any implications

arising under s 5(b) of the Act. To provide context to the findings in this assessment, a description of

the Māori world view and the relationship of Māori with their environment is included as Appendix A.

Ngā here ture (Statutory obligations)

Section 5(b) provides that to achieve the purpose of the Act, the decision maker must recognise and

provide for the maintenance and enhancement of the capacity of people and communities to provide

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for their own economic, social, and cultural wellbeing and for the reasonably foreseeable needs of

future generations.

Section 6(d) of the Act obliges all persons exercising functions, powers, and duties under the Act, to

achieve the purpose of the Act, to take into account the relationship of Māori and their culture and

traditions with their ancestral lands, water, sites, waahi tapu, valued flora and fauna, and other taonga.

In accordance with section 8, the decision maker is required to take into account the principles of the

Treaty of Waitangi (Te Tiriti o Waitangi).

The Treaty principles most relevant to assessing and deciding this application are:

The principle of active protection of Māori interests.

The principle of partnership.

Assessment of impacts on cultural receptors

Impact on Papatūānuku (Land and soils)

For those Māori who participate in the trial, they may wish to have their cells that are no longer

needed, returned to papatūānuku. Mātauranga Māori recognises that life comes from papatūānuku

and so our bodies, or anything that is from the body, should be returned to papatūānuku.

Impact on Ngā otaota (Plants)

The use of CAR T-Cells is not likely to impact on Ngā otaota.

Impact on Ngā manu, me ngā ngārara (Birds and reptiles)

The use of CAR T-Cells is not likely to impact on Ngā manu me ngā ngārara.

Impact on Te Aitanga Pepeke (Arthropods)

The use of CAR T-Cells is not likely to impact on Te Aitanga Pepeke.

Impact on Ngā wai koiora (Aquatic habitats)

The use of CAR T-Cells is not likely to impact on Ngā wai koiora.

Impact on Taha hauora (Human health and well-being)

The use of CAR T-Cells has the potential to have a positive impact on Taha hauora for those who

participate in the trial. It has the potential to improve the health of the patients that are involved.

The safety measures that will be employed, will limit any negative impacts to those outside of the trial.

Impact on kaitiakitanga and manaakitanga (resource guardianship and due care)

The use of CAR T-Cells is not likely to impact on kaitiakitanga and manaakitanga.

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Ngā hua (Benefits)

There will potentially be health benefits to those Māori who participate in the trial.

Analysis of impact

The benefits to Māori associated with this application are likely to outweigh any detrimental impacts to

Māori.

The controls proposed to be assigned to CAR T-Cells should be sufficient for managing the impact of

any negative effects on Māori.

The overall impact on the relationship Māori have with their environment and taonga is likely to be

negligible, and is unlikely to adversely affect the ability of Māori to exercise kaitiakitanga.

The overall impact on Māori economic wellbeing (arising from the impact on the environment and

taonga) is likely to be negligible.

The overall impact on Māori social wellbeing (arising from the impact on the environment and taonga)

is likely to be negligible. This includes impacts on Māori ways of life and taha hauora (human health

and well-being).

The overall impact on Māori cultural wellbeing (arising from the impact on the environment and

taonga) is likely to be negligible so long as the Māori participants are able to dispose of their cells in

accordance with their Tikanga.

Te Tiriti o Waitangi

The Principles of the Treaty of Waitangi have been considered in relation to this application and no

concerns arise under the Treaty Principles, as summarised below.

The decision makers on this application are making a decision informed by a Māori perspective.

The EPA considers it is acting in good faith, and is acting reasonably and fairly, in respect of this

application. Mātauranga Māori and tikanga Māori are being respected.

Kupu whakatepe (Conclusion)

Impact on the maintenance and enhancement of the capacity of people and communities to provide for their own economic, social and cultural well-being

This application is not likely to affect the ability and capacity of Māori to maintain their economic and

social well-being. However, the cultural well-being may be affected by the application. The application

does not mention that the cells of the participants can be disposed of how the participants would like

them to. The Māori participants may prefer to have their cells buried in their rohe, in accordance with

Tikanga. Māori have a connection with the whenua (land) and their cultural well-being includes having

their bodies and body parts, returned to the whenua. This is something that can be discussed with the

participants.

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Impact on the relationship of Māori and their culture and traditions with their environment and taonga

This application is not likely to significantly affect the relationship of Māori and their culture and

traditions with their environment and taonga, including culturally significant species, resources, and

places, and the customary values, practices and uses associated with these taonga.

Treaty of Waitangi principles

The active protection principle: the Crown has a duty to actively protect Māori interests.

No issues arise because Māori interests can be considered by Māori that are participating in the trial.

The informed decision making principle: the Crown has a duty to make informed decisions.

No issues arise. The EPA is making an informed decision because of the Māori perspective that is

being provided in this report.

The partnership principle: to act fairly, reasonably, and in good faith.

No issues arise. The EPA is acting reasonably and in good faith because it is considering a Māori

perspective for the application.

Dated: 19 August 2019

57. Finally, we also note that the applicant submitted a detailed application of their proposed clinical

trial to the Research Advisory Group-Māori (RAG-M) of the Capital & Coast District Health Board

(CCDHB). This application was endorsed by the RAG-M (Appendix 1). We further note, in relation

to the point regarding disposal of the cells in the above assessment, the trial participants’ cells

cannot be returned to them because of health and safety regulations. In the RAG-M endorsement

of the clinical trial, that the applicant intends to use a consent form that enables Māori participants

in the ENABLE trial to specify a karakia to be spoken upon the 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 58. The Department of Conservation (DOC), the Ministry for Primary Industries (MPI) and Medsafe

were given the opportunity to comment on the application.

59. Medsafe provided information regarding the regulations and guidelines pertaining to facilities

involved in aspects of GMP procedures (Medsafe, personal communication). Medsafe further

stated that it had no comments to make regarding the application for the release of WZTL-002

cells as qualifying organisms and that the Health Research Council’s Standing Committee on

Therapeutic Trials (SCOTT), which has responsibility for approval of clinical trials under the

HSNO Act, had approved the trial.

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60. DOC replied that they believed that the proposed release of WZTL-002 cells had no biodiversity

implications, and that they had no objection to the approval of the application.

61. MPI had no comment on the application.

Legislative criteria to be considered 62. Section 38I of the HSNO Act provides for the rapid assessment of applications that seek to

release qualifying organisms. A qualifying organism is, in part, a new organism that is or is

contained in a medicine (as defined in section 3 of the Medicines Act 1981).

63. WZTL-002 cells are a medicine as it is “for administering to 1 or more human beings for a

therapeutic purpose, and achieves, or is likely to achieve, its principal intended action in or on the

human body by pharmacological, immunological, or metabolic means” (in accordance with section

3 of the Medicines Act 1981).

64. In order to be approved for release as a qualifying organism, section 38I(3) of the HSNO Act

requires that the decision-maker be satisfied that, taking into account all the controls that will be

imposed (if any), it is highly improbable that:

a) the dose and routes of administration of the medicine would have significant adverse effects

on-

i) the health of the public; or

ii) any valued species; and

b) the qualifying organism could form an undesirable self-sustaining population and would have

significant adverse effects on-

i) the health and safety of the public; or

ii) any valued species; or

iii) natural habitats; or

iv) the environment.

65. In doing so, the effects of the medicine or qualifying organism in the person who receives the

medicine are not to be taken into account as per section 38I(4) of the HSNO Act.

66. In the first instance, we have assessed the organism against these criteria, as set out in the

following section of this report.

67. If the organism is not considered to meet these criteria, the applicant may request that the

application be considered under section 38, or section 38A.

Assessment of the risk of WZTL-002 cells conditional release against legislative criteria

68. It is highly improbable that the dose and administration of WZTL-002 cells will have significant

adverse effects on the health of the public or any valued species, given that:

The LV-1928T2z lentiviral vector used to create WZTL-002 cells is produced and verified to

lack replication-competent lentiviral vectors in containment under EPA approval (application

APP203214)

The WZTL-002 cells produced after transduction by the LV-1928T2z lentiviral vector are

further verified to lack replication-competent lentiviral vectors (RCLs) in containment under

EPA approval (application APP203214)

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Screening of WZTL-002 cells for sterility/safety testing will be carried out at Wellington SCL,

an IANZ-accredited testing facility, as a contractor under a Medsafe-issued licence to

manufacture WZTL-002 cells

WZTL-002 cells are not directly shed by recipients

WZTL-002 cells will be handled and disposed of by trained medical personnel in accordance

with accepted medical practices as a medicine used in a clinical trial for specific patients

The use of WZTL-002 cells in a Phase 1 clinical trial in New Zealand is not likely to

significantly affect the relationship of Māori and their culture and traditions with their

environment and taonga, including culturally significant species, resources, and places, and

the customary values, practices and uses associated with these taonga

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 a study protocol

exclusion criterion under section s30(3) of the Medicines Act.

New Zealand Blood Service screening procedures prevent blood donations from patients who

have ever had leukaemia and/or lymphoma.

69. Moreover, it is highly improbable that WZTL-002 cells could form an undesirable self-sustaining

population that would have significant adverse effects on the health and safety of the public, any

valued species, natural habitats or the environment, given that:

WZTL-002 cells cannot survive for extended periods of time outside a host organism without

human intervention

WZTL-002 cells are not free-living organisms in the environment

WZTL-002 cells are easily destroyed by heat, desiccation, ultraviolet light, bleach, household

disinfectants, and detergents.

WZTL-002 cells are autologous, ie, derived from a single person, and as such have

immunological markers that would result in the immune system of a recipient other than the

patient from which they were derived to destroy them, and thus they cannot be transmitted

amongst animals or humans.

70. If the applicant receives approval from EPA for the release of WZTL-002 cells, they must submit

an application to Medsafe for the use of the cells in a Phase 1 clinical trial at Wellington Hospital.

Per 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).

71. We acknowledge that all medical practitioners administering vaccines in New Zealand are

expected to do so in accordance with the standards set out in the Ministry of Health’s Guideline

on the regulation of therapeutic products in New Zealand Part 11 (Ministry of Health 2018b),

which specifies the requirements for regulatory approval and good clinical practice in clinical trials.

Proposed controls 72. The applicant has proposed two sets of controls in the ‘Risks, costs and benefits’ subsection

within section 3.2 of the application. These detailed controls broadly pertain to how the cells may

be used and disposed of, both in sterility testing at Wellington SCL, as well as within the trial itself.

However, as discussed in paragraphs 28-32, as well as paragraphs 38-54, we consider that the

proposed controls will be fully covered either by the applicant’s study protocol, as required for

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EPA staff assessment report for application APP203750

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clinical trials under section 30(3) of the Medicines Act, and/or the applicant’s Licence to

Manufacture, and/or the New Zealand Code of Good Manufacturing Practice, all of which are

administered by Medsafe and assessed by the Health Research Council of New Zealand.

Therefore, we consider the imposition of the applicant’s proposed controls under the present

application would be redundant to those of the Medsafe-issued clinical trial approval (if granted)

and/or Licence to Manufacture the WZTL-002 cells.

73. We consider that the primary risk of this trial from an environmental perspective is the

unintentional creation of a replication-competent lentiviral vector. As detailed in paragraphs 21-26,

third generation lentiviral vector systems are extremely safe, and a RCL has never been detected

over the more than 25 year history of their use. We consider that what little risk remains with

regard to the unintentional creation of an RCL is dealt with either in the applicant’s existing

development approval (APP203214) for the creation of the LV-1928T2z vector, and/or the

applicant’s Medsafe-issued Licence to Manufacture WZTL-002 cells (discussed in paragraphs 30

and 69).

74. Regardless of the above, and although we consider it highly improbable that any adverse

environmental effects will eventuate from the release of WZTL-002 cells, we consider that it is

appropriate to impose certain controls on the application due to the experimental nature of the

therapy.

75. Our proposed controls (detailed in paragraph 79) specify requirements for notifications of both the

beginning and the end of the trial, limitations on the points of release of the cells, as well as a

limitation on the duration of the EPA approval, if granted.

International obligations 76. Should this application be approved, the approval for the release of WZTL-002 cells must be

reported to the UN Convention on Biological Diversity’s Biosafety Clearing House1, as required by

Article 20 of the Cartagena Protocol for Biosafety, to which New Zealand is a Party. This risk

assessment, as well as the decision document, must also be provided to the Biosafety Clearing

House.

Conclusion and recommendation 77. Based on the intrinsic properties of both WZTL-002 cells, the third generation lentiviral vector from

which they are derived, the quality assurance and quality control measures that will be undertaken

by the applicant under its existing development approval APP203214, the accreditation of the

laboratory to be used for safety and sterility testing of the WZTL-002 cultures, as well as the

general biological characteristics of CAR T-cells, we consider it highly improbable that WZTL-002

cells will establish a self-sustaining population, or have any significant adverse effects on the

health and safety of the public, any valued species, natural habitats or the environment.

78. Thus, we recommend that this application to release WZTL-002 cells be approved, subject to the

following controls.

Control 1 – The New Zealand sponsor of the Phase 1 clinical trial must provide EPA and MPI

with a written notification that work has commenced under this approval within one

1http://bch.cbd.int/

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week after the first release of WZTL-002 cells for testing at Wellington Southern

Community Laboratories (Wellington SCL).

Control 2 – The organism (WZTL-002 cells) must only be released for safety and sterility testing

to:

Wellington SCL (Wellington Hospital Site), Newtown, Wellington.

Control 3 – The organism (WZTL-002 cells) must only be administered:

to patients who are enrolled in a Phase 1 dose escalation study clinical trial (the

ENABLE trial) approved under the Medicines Act 1981 to examine the safety and

efficacy of WZTL-002 cells in patients with relapsed or refractory B-cell non-Hodgkin

lymphoma at Wellington Hospital.

Control 4 – The New Zealand sponsor must provide EPA and MPI with a written notification of

the conclusion of the Phase 1 clinical trial, within one month of its conclusion,

whereupon this approval will expire.

79. We note, and the Malaghan Institute for Medical Research recognises, that an approval for a

qualifying medicine granted under section 38I of the HSNO Act is not an approval to use that

medicine until it has been lawfully supplied for use under the Medicines Act 1981.

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Weng J, Lai P, Qin L, Lai Y, Jiang Z, Luo C, Huang X, Wu S, Shao D, Deng C and others 2018. A

novel generation 1928zT2 CAR T cells induce remission in extramedullary relapse of acute

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Appendix 1: Endorsement of WZTL-002 clinical trial by the Research Advisory Group-Māori of the Capital & Coast District Health Board

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