Securing the Safety of Cell Therapies to Realize their Potential

Transcription

1 Securing the Safety of Cell Therapies to Realize their Potential Identify and Optimize Novel Technology to Evaluate Cell Therapy Safety, Mode of Action and Efficacy. HESI Annual Meeting June 10, 2015

2 Presenters Dr Bill Shingleton Technical Lead, Core Imaging R&D, GE Healthcare Life Sciences. Dr Greg Mullen, Senior Lecture in Imaging Biology/Radiopharmceutics, Department of Chemistry & Biology, Kings College London. 2

3 Aim of the Project: Identify, develop and promote novel technology that will enable the progression of cellular therapies to approved, licensed treatments. Technologies that will perform the equivalent role of conventional drug development safety assays in the cell therapy space. 3

4 Drug Development Pathway Idea Molecule synthesis Pre-clinical Manufacture Clinical Trials Small Molecule Safety, DMPK, ADME Large Molecule Safety, DMPK, ADME Cell Therapy Allogeneic? Safety, DMPK, ADME Autologous? Safety, DMPK, ADME 4

5 Determining the Un-Met Need For cell therapy, an IND is a very different challenge to small molecule or large molecule INDs. Scientific advances continue apace. Evidence of clinical benefit is building. Large Investment in up-stream bioprocessing and manufacture Immunotherapy Trials Registered Stem Trails by Disease (May 2015 n=4965) Cancer Graft vs Host Cardiac Brain Infection Autoimmune 5

6 Areas of Safety Concern 1. Pluripotent cells developing into tumours i. Mesenchymal stem cells promoting existing, undetected tumours. 2. Immunogenicity/Inflammation associated with transplanted cells. 3. Loss of phenotype/efficacy during expansion and manufacture. 6

7 How to address the concerns Need to be able to follow the therapeutic cell. Test to ensure correct level of potency. Validate data against current biochemical, cytological and histopathology techniques. Link cell behaviour to mode of action and efficacy. 7

8 Methods we could employ - Flow Cytometry Very well established. Readily available and affordable commercially. Could be the bench-mark for validation. Enables correlation of phenotype to outcome Not a predictor of potency. Not a measure of cell behaviour No in-vivo localaisation. 8

9 Techniques we could employ - Molecular analytics Soluble mediators High throughput, available, cost effective. Proof of origin? Where or when. No in-vivo localisation data. mrna Barcoding Emerging technology. Cell specific to tissue of origin. Low volumes. No in-vivo localisation data. 9

10 Techniques we could employ - Fluorescence and microscopy Microscopy Cell and tissue based techniques would map to established DMPK methodology. High throughput/low volume technology is available. Requires biopsy, no real-time in-vivo localisation. Fluorescence imaging Sensitive, available, cost effective. Could be combined to aid surgical direction. Provides in-vivo localisation (Small Animal Only). 10

11 Regulatory pull for cell tracking tools US FDA - Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products, July 2013 US FDA - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products, November 2013 EU EMA - Reflection paper on stem cell-based medicinal products, January 2011 EU EMA CHMP GUIDELINE ON HUMAN CELL-BASED MEDICINAL PRODUCTS, May 2008 Health Canada - Draft Guidance Document: Guidance for Sponsors: Preparation of Clinical Trial Applications for use of Cell Therapy Products in Humans, October 2014 Regulatory Agencies recognize the importance of distribution, migration of cells, but the inadequacy of the conventional PD/PK methodologies; recommend using imaging technologies to track cells as appropriate 11

12 A potential solution? An introduction to non-invasive imaging and how it could be applied to address cell therapy safety concerns. 12

13 What would such tools do to help in the clinical development of cellular therapies? Phase 1 clinical trials will monitor safety & immediate localisation of cells post injection. Trials will be dose escalating starting with a micro-dosing group to determine in vivo localisation of cells and address the following questions: Do the cells localize to the expected sites? What is the optimal route of administration? How many cells survive administration? What is the extent of engraftment? What is the ideal dosage scheme? Is there any early off target localisation? if so where, how much and is this a significant problem? How long do the cells remain at the engraftment site (< 2 weeks)? 13

14 How can cell tracking help in the clinical development of cellular therapies? Phase 2 clinical trials will monitor long term safety, mechanism of action and generate surrogate endpoints for evaluating efficacy of cellular therapy: How long do the cells survive in vivo (< 2 weeks)? How long do they remain at site of engraftment? (Weeks to months)? Do you see any late off-target localisation? Are the cells proliferating? 14

15 Imaging Contrast Agents for Cell Tracking Cu-64-PTSM Zr-89-Oxine 15

16 Non-clinical Evaluation of Cellular Therapies MR cell tracking of human cord blood derived CD34 + stem cells to the bone marrow of athymic mice Femur Sacrum Unlabelled CD34 Stem Cells Labelled CD34 Stem Cells Before Injection 2 hrs 24 hrs Niemeyer et al, European Radiology,

17 Wholebody Non-Invasive Imaging Modalities For The Evaluation of Cellular Therapies Tracking In-111 labelled MSCs in Liver Cirrhosis Following intravenous infusion, the labeled MSCs first accumulated in the lungs, and gradually shifted to the liver and spleen during the following hours to days. Gholamrezanezhad et al, Nuc. Med. Bio.,

18 Wholebody Non-Invasive Imaging Modalities For The Evaluation of Cellular Therapies Neutrophils 1 min 5 min 15 min 25 min 120 min Eosinophils Lung Liver Spleen 4hrs SPECT Eosinophils Neutrophils Lukawska et al, JACI,

19 Example of where imaging would have helped in the safety evaluation of cellular therapy MAGE-A3 CAR T-cell therapy What happened? Fatal cardiotoxicity and neurotoxicity Cross-reactivity with unrelated peptides Non-specificity was not observed in extensive nonclinical testing but subsequently discovered after additional in vitro analysis How could cell tracking have prevented this? Early cell tracking of off-target localisation. Longer-term imaging would have shown off-target cell proliferation by amplification of imaging signal overtime 19

20 Next Steps 20

21 Outline project plan Milestone 1 (12 months) Set up and conduct a symposium with industry, regulators and academic communities with the aim to: 1) Identify and engage with like-minded organisations and working groups. 2) Establish what success criteria are and gain consensus on where greater consistency could be achieved. OUTPUT: White Paper Milestone 2 (12-36 Months) Identify any potential technologies (appropriate to target disease) that could deliver a test aligned to agreed success criteria. Design and complete preliminary validation of the proposed technology for suitability to stem cell preclinical and potentially clinical investigations. Engage regulators to establish acceptance criteria for such tools to support stem cell development as therapeutic agents. 21

22 Organisations who wish to join so far. GE Healthcare Kings College London Cardiff University Celsense Cell Therapy Catapult (UK) Karolinska Hospital and UKRMP Alliance for Regenerative Medicine (ARM) International Society for Stem Cell Research (ISSCR) Brings together existing members of HESI and new organisations. 22

23 Who to ask to join a consortium? Regulatory Authorities Therapy developers Academic, biotech, hospitals, pharma. Healthcare providers Facilities to deliver (hardware and expertise) Reimbursement We may have tools to try, but the above organisations have the experience and knowledge to apply them. 23

24 Thank you for your attention. Any questions? 24

25 Appendix 25

26 Regulatory pull for cell tracking tools US FDA - Draft Guidance for Industry: Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products, 7/ Special Monitoring Considerations for CGT Products For CT products, if applicable, the potential for migration from the target site, ectopic tissue formation, or other abnormal cell activity should be addressed by performing evaluations appropriate to the nature of the concern (e.g., imaging studies for potential ectopic tissue or cardiac rhythm monitoring for potential arrhythmogenic foci in cardiac disease CGT studies). 26

27 Regulatory pull for cell tracking tools US FDA - Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products, November Distribution As a consequence of their biologic attributes, CT products administered in vivo are not subject to conventional chemical analyses; therefore, standard ADME and pharmacokinetic testing techniques and profiles are not applicable. Although influenced by specifics of the CT product and its ROA, cells have an inherent potential to distribute to sites other than to the target organ/tissue. Various methods, such as imaging modalities used for detection of radioisotopelabeled cells, genetically modified cells (e.g., expressing green fluorescent protein), nanoparticlelabeled cells (e.g., iron-dextran nanoparticles), or the use of polymerase chain reaction (PCR) analysis and immunohistochemistry to identify cells of human origin or cells of a karyotype different than the host (e.g., gender), have been used to assess distribution. A potential advantage of in vivo imaging techniques is that in many instances, the same animal can be evaluated over time, thus decreasing variability and reducing the number of animals used. Data should be provided to support the viability and function of the CT product if the cells are modified to enable use of such imaging techniques. 27

28 Regulatory pull for cell tracking tools EU EMA - Reflection paper on stem cell-based medicinal products, January Biodistribution and niche Due to limitations with current methodologies, adequate information cannot be obtained concerning biodistribution from human studies. Therefore, nonclinical biodistribution studies of stem cells are considered highly important. The design of the biodistribution studies should take into account that the stem cell fate is a multi-step process (i.e. migration, niche, engraftment, differentiation and persistence). Suitable methods for tracking of stem cells should be applied where these methods are available, e.g. introducing marker genes or labelling of cells Pharmacokinetics It is acknowledged that it may be challenging to perform biodistribution studies in humans (fate of the stem cell transplant in the body) due to the current lack of appropriate techniques. However, depending on the risk profile of the product and its mode of and site for administration, these studies may be important and their absence should be justified. The sponsor is encouraged to develop and validate new non-invasive methods for biodistribution studies in humans to follow the cells during the clinical studies. Possible markers / tracers should be evaluated and justified. 28

29 Regulatory pull for cell tracking tools EU EAM CHMP GUIDELINE ON HUMAN CELL-BASED MEDICINAL PRODUCTS, May Pharmacodynamics Even if the mechanism of action is not understood in detail, the main effects of the CBMP should be known. When the purpose of the CBMP is to correct the function of deficient or destroyed cell/tissue, then functional tests should be implemented. If the intended use of the CBMP is to restore/replace cell/tissues, with an expected lifelong functionality, structural/histological assays may be potential pharmacodynamic markers. Suitable pharmacodynamic markers, such as defined by microscopic, histological, imaging techniques or enzymatic activities, could be used Pharmacokinetics Conventional ADME studies are usually not relevant for human CBMP. Study requirements, possible methodologies and their feasibility shall be discussed, attention being paid to monitoring of viability, proliferation/differentiation, body distribution / migration and functionality during the intended viability of the products. 29

30 Regulatory pull for cell tracking tools Health Canada - Draft Guidance Document: Guidance for Sponsors: Preparation of Clinical Trial Applications for use of Cell Therapy Products in Humans, October 2014 Traditional pharmacokinetic studies to assess bio-distribution in humans may be challenging for cell therapy products and may require the development of appropriate cell tracking technologies. The presence of cells in non-target sites should be further investigated and the risks fully evaluated whenever feasible. Health Canada may insist on pharmacokinetic assessment for cell therapy products associated with higher risks of tumourigenicity or ectopic tissue formation prior to the initiation of trials in a large number of patients. 30

31 Stem Cell Clinical Trials Search clinicaltrials.gov for Stem Cell 4965 hits Trials by Phase Stem Trails by Disease Phase 0 Phase 1 Phase 2 Phase 3 Phase 4 Cancer Graft vs Host Cardiac Brain Infection Autoimmune One study approved for marketing! GE/KCL HESI Proposal 6/15/2015

32 Determining the Un-Met Need Market size for cell bioprocessing: Massive investment in the manufacture of cell therapies. Regulatory compliant, clinically relevant and cost effect manufacture is the current focus. Proof of patient safety will be needed to capitalise on this investment. Cell Therapy $3 BN Cell Bioprocessing (incl. commercial) $710M Cell Bioprocessing Trials Only $323M Autologous Trials $240M Autologous Cellular Immunotherapy $203M 32

33 Example of where imaging would have helped in the safety evaluation of cellular therapy MAGE-A3 CAR T-cell therapy What happened? Fatal cardiotoxicity Cross-reactivity with unrelated peptide from Tintin protein in the heart. Fatal neurotoxicity Cross-reactivity with an undiscovered MAGE-12 protein Non-specificity was not observed in extensive nonclinical testing but subsequently discovered after additional in vitro analysis 33

34 Example of where imaging would have helped in the safety evaluation of cellular therapy MAGE-A3 CAR T-cell therapy How could cell tracking have prevented this? Early cell tracking of off-target localisation. Longer-term imaging would have shown off-target cell proliferation by amplification of imaging signal overtime Use a suicide gene which doubles up as imaging reporters Performed a non-therapeutic cellular micro-dosing study to look at localisation of non-therapeutic dose 34