These treatments are expensive and, at least in the US, subject to the FDA’s REMS programme limiting their use to certified healthcare facilities, owing to complex administration cell therapy guidelines from manufacturer as well as serious potential side effects such as cytokine release syndrome, macrophage activation syndrome and neurotoxicity. For autologous CAR-T products, manufacturing costs, logistics and hospital costs are very high, not least because of the management of patient chain of custody and the coordination of multiple institutional departments, such as the apheresis and transplant units, etc.
But things are changing rapidly with the advent of allogeneic approaches, whether they be cells derived from HLA typed and matched healthy donors (marrow or peripheral), or from gene edited donor cells which have been modified to allow them to be given to non-HLA matched patients or TAC-T cells (T-Cell antigen coupler). These approaches have the possibilities of therapies with potentially reduced safety concerns, a potentially higher therapeutic index, as well as breadth of targets including solid tumours.
Allogeneic CAR-T cells can be manufactured using T-Cells from just one, single healthy donor and can be used in multiple patients. Estimates from studies suggest that a single donor set may be sufficient to create therapeutic doses for over 200 average adult subjects.
That said, there will be limitations on how much cells from a single donation can be expanded necessitating multiple donations from one donor or different donors for large scale production, thus introducing some variability, so how products compare between donors/donations will need further investigation. Nonetheless this ‘off-the-shelf’ technology approach will almost certainly reduce manufacturing, logistics and hospital treatment costs as well as broadening the range of tumour targets in the medium to long-term.
There are techniques that use allogeneic CAR-Ts from a genetically matched donor which might overcome the issue of rejection and T-Cells might sustain longer in the body as they are not recognised as foreign. Genes in healthy donor T-cells are more commonly edited using gene technology like ZFNs, TALENs and CRISPR–Cas9. Using this approach, allogeneic CAR-T cells can be engineered to stop expressing endogenous T cell receptor (TCR) and/or major histocompatibility complex (MHC) moieties, helping to avoid graft-versus-host disease (GVHD) or rejection.
Tumour cell contamination is also a potentially serious problem where patients with refractory disease often have circulating leukaemia cells in the peripheral blood which are harvested during the leukapheresis process. While these tumour cells may be targeted for killing when the cells are modified in the manufacturing step, the success is not guaranteed and can impede the efficacy of CAR-T cells.
Allogeneic approaches may have the capability to be more exact with there being more uniform starting materials sourced from healthy donors creating possibilities for more predictable safety and efficacy.
The success of autologous CAR-T production can be limited solely due to logistics and/or manufacturing implications. We know from experience that there are a number of ACT autologous therapies that do not reach the patient for treatment due to a failure in one of the many supply chain processes. In studies of Kymriah in ALL and in lymphoma, between 7% and 9% of studied patients didn’t receive the CAR-T product due to manufacturing failure.
Additionally, the success of autologous CAR-T production can be limited due to clinical implications, where, for example, patients are unable to produce sufficient T-Cells, or, due to the production time post-apheresis, patients suffer disease progression and fall out of eligibility before the CAR-T cells can be infused. As donor cells are not affected by supply issues to the same extent and the production times are less limiting, allogeneic approaches overcome numerous impediments to a large degree.
T-Cell malfunction is a known factor in cancer patients. It has been described that healthy donor T-Cells are more viable and potent than T-Cells from cancer patients, so the response rate for allogeneic T-Cells might well be higher. In autologous T-Cell studies, there are substantial proportion of patients who discontinue before lymphodepletion and infusion due to disease progression, death or infection. Donors with a T-Cell phenotype associated with superior T-Cell function can be identified, increasing the quality of the end product.
While gene editing methods are revolutionising cell therapy, such highly modified products come with unknown risks.
Off target effects can occur and create potentially cancerous events. Monitoring safety data in allogeneic approaches has the same imperative as for autologous treatments.
We still need to do a lot more research to establish the relative durability of allogeneic CAR-T cells however we do know that it is far easier to give patients additional infusions of allogeneic cells if the T-Cells become exhausted. So even if there may be some challenges with sustainability of foreign T-Cells, the allogeneic constructs will likely overcome the barrier of patients being unable to produce CAR-T cells.
There is ongoing development of decentralised autologous cell manufacturing whereby hospitals could process autologous T-Cells locally using such instrumentation as the Clinimacs Prodigy System. The prospects for applying this approach with allogeneic T-Cells is arguably more powerful as it offers the advantage of dispensing with transportation risks and costs while enabling a local stock of usable cells.
In summary some of the clinical/technical prospects for allogeneic approaches providing their advantageous distinction over autologous CAR-T cells include: broadening the range of target cancer types, including new approaches for solid tumours; overcoming T-cell exhaustion with possibilities of greater durability and/or prospects for multiple infusions; increased volume of usable cells; easier sourcing of cells from donors with concomitant “improved quality” of T-cells; cutting wait times between lymphodepletion and infusion; more efficient manufacturing and last but by no means least, costs should come down significantly. When costs fall, patient accessibility increases, which is the ultimate goal.
Studies will become faster paced as there will be less waiting time for patients to receive infusions. The patient slot management algorithm is simplified and there will be less delay in waiting for manufacturing slots, which has been a hallmark of autologous CAR-T trials.
Supply chain logistics are changed as we relegate the pre-eminence of vein to vein product tracking. Product delivery to patient is considerably simplified and is more akin to conventional investigational product supply. However, we are introducing a new element of donor cell management with appropriate approval becoming a key factor. In this regard we must anticipate the greater engagement of transplantation centres conducting allogeneic stem cell transplant (ASCT) outside of the trial hospital. Although, autologous approaches do already engage with apheresis centres within the trial hospitals.
There are also regulatory implications to take into account. In order to have donor T-Cells, the clinical trials will have to access FDA registered donor centres that meet all cGMP and cGTP standards. Donor centres will need IRB-approved protocols and informed donor consents that adhere to FDA, EMA, PMDA and other applicable regulatory requirements. Additionally, they should maintain compliance with any pertinent State, Federal or national accreditation standards, FACT/JACI to ensure the accuracy and reliability of quality control testing, and verify an appropriate quality management system and controlled collection processes.
Adding re-treatment possibilities to allogeneic studies, rarely seen in autologous studies, will likely increase clinical trial duration and generate entirely new data sets and further increase data volumes. As mentioned earlier, we are still attempting to elucidate durability in the allogeneic sphere as well as new safety factors be they GVHD, HVGD (rejection) or any host of unknown factors We also need to gain greater understanding of Maximum Tolerated Doses (cell volumes) which will likely vary considerably between tumour targets and specific constructs.
With a bolus of new targets, especially with the emerging T-cell engineering technology, there will be increasing competition impacting trial site people resource that could put stresses on patient recruitment potential.
All of this is underpinned by the exciting prospect of there being so much more to be explored in allogeneic T-cell clinical trials. Aside from the obvious need for increased clinical trials in more patients to assess the efficacy and toxicity we will also need more long-term follow-up to monitor the rate of acute and chronic GVHD, rejection, T cell exhaustion/ senescence, and target antigen escape. Finally, there is the likelihood of more combinational allogeneic CAR-T cell trials with T-cells given either concomitantly or sequentially to target multiple antigens in one type of cancer. More trials, more patients, more complexity and more hope.
Martin Lachs is VP project management oncology and Cell Therapeutics at ICON, heading up the global therapeutic operational team, and is at the helm of the ACT group. With 27 years’ experience in clinical research and development he holds a Research PhD on Breast Cancer Cell Biology. Martin is based in London, UK.
Olivier Saulin is a Biochemistry MSc major based in France and has over 17 years drug development experience. In the last 5 years, Olivier has built up significant hands-on expertise in gene and cell therapy clinical development. Olivier is one of ICON’s ACT Principal Program Managers.
Brandon Fletcher is based out of Oregon in the US and has 27 years of research experience, including extensive academic, pharma and CRO roles in multiple immuno-oncology research arenas. Brandon is one of ICON’s ACT principal program managers.
ICON plc is a global provider of outsourced drug development and commercialisation solutions and services to the pharmaceutical, biotechnology, medical device and government and public health organisations. The company specialises in the strategic development, management and analysis of programmes that support clinical development – from compound selection to phase I-IV clinical studies. With headquarters in Dublin, Ireland, ICON currently operates from 90 locations in 37 countries and has approximately 14,000 employees. Further information is available at www.iconplc.com
For more information on ICON Commercialisation and Outcomes Services visit: www.ICONplc.com/commercialisation