However, as is the case with many other paradigm-shifting technologies, it has been a long and bumpy road with many more twists and turns than expected. Most of these initial advances have been built on the use of αβ T cells engineered to express chimeric antigen receptors (CAR-Ts), but more recently the field has rapidly expanded to include a number of difference cell sources and engineering approaches. Regardless of which route people are trying to take in this field, the key hurdles can be roughly broken down into:
3) manufacturability, and
The first two of these hurdles are mostly biological and have attracted the most effort and risk-capital with significant breakthroughs in our understanding and capabilities. However, in this short post I’d like to focus on the latter two categories, which I feel encompasses a set of often overlooked challenges that exemplify just how hard it is to effectively translate scientific breakthroughs to real-world patient impact.
It also gives me great pleasure to know that here at the UCL Technology Fund we’re working with a number of world-renowned UCL academics on several (undisclosed) projects that are trying to tackle these very issues on multiple different fronts.
Using allogeneic approaches to lower cost and improve manufacturability
Instead of relying on patient-derived autologous treatments, being able to create ‘off-the-shelf’ donor-derived allogeneic treatments has long been touted as one of the key catalysts for unleashing the full impact and reach of cellular immunotherapies within cancer.
While I’m aware that allogeneic approaches also help overcome significant hurdles within efficacy and persistence, it can be argued that the real reason it has garnered so much attention within the field is the impact it would have on quality control (QC), cost-of-goods (COGs), and delivery of treatments. The use of allogeneic cell sources or facilitating technologies would enable treatments to be manufactured in advance with economies of scale, quality-checked and cryopreserved for timely administration to the sickest patients in non-specialist clinical settings. One estimate suggests that switching from an autologous manufacturing method to an allogeneic one would reduce the COG/dose from ~$96k to $4.5k (see here). This would dramatically shift the bespoke and constrained model of existing autologous treatments, which makes it fundamentally unscaleable to a larger population.
However, this approach consequently brings its own technical hurdles. One major challenge is that of graft-versus-host disease (GvHD) where the T-cell receptor (TCR) of the allogeneic product recognises antigens in the recipient and starts attacking normal tissue. A second challenge is the potential for rejection of the donor cells by the recipient’s immune system (host-versus-graft, HvG). In this situation, human leukocyte antigen (HLA) molecules on the surface of donor T cells are recognised as ‘foreign’ and the cells targeted for elimination, thereby potentially limiting anti-tumour efficacy after administration.
A number of (extremely) well-funded companies (see: Allogene Therapeutics, CRISPR Therapeutics and Cellectis) are trying to overcome this issue by using genome editing tools such as TALENs or CRISPR/Cas9 nucleases to knock-out both the native TCR and the expression of HLA molecules on the cells. Although these companies have recently posted impressive clinical results with each of their platforms, the jury is still out regarding the long-term safety concerns of using genome editing tools (see here for the most recently identified concern with CRISPR). In light of this, other groups are now trying to develop non-genome editing based approaches to generating allogeneic CAR-Ts that could side-step this issue completely (see here for an MRC-funded clinical trial led by UCL researchers that is due to start in 2021).
Using alternative cell types to side-step the issue or alloreactivity
Although the majority of immunotherapy approaches are based on the canonical αβ T cell type, others have instead chosen to explore the full repertoire of alternative immune cells as a chassis for treatments.
The most widely used are natural killer (NK) cells and gamma delta (γδ) T cells, which both exhibit natural cytotoxicity towards tumours and are readily engineerable by CAR and other approaches, but importantly do not induce GvHD due to their differing TCR-interactions. Due to this, some argue that engineered NK cells and γδ T cells would make more appropriate starting material for cellular immunotherapies as they could be just as effective but cheaper and easier to manufacture given their inherent allogeneic capabilities. While a number of exciting companies are diligently exploring these alternative cell types in the clinic, they are playing catch-up to their αβ T cell peers who will not be relinquishing their head-start any time soon (see here for a recent review of the clinical landscape).
Tackling the problem of manufacturability and cost by other (necessary) means
The manufacturing process for cellular immunotherapies is complex, multi-process and fraught with failure points. Others have already realised that the entire process itself needs overhauling, regardless of which cell type is used.
Some, for example, are trying to completely overhaul the primitive methods we use for cell culturing through hardware advancements (see Mytos and Ori Biotech), while others are trying to use software to unshackle us from what is still unbelievably a predominantly paper-based process (see Autolomous). Given the critical (and expensive) step of viral transduction within the CAR-T manufacturing process, others are trying to chip away at this substantial cost through the use of viral transduction enhancers to minimise the amount of vector needed for each dose (see Sirion Biotech’s LentiBOOST or Takara Bio’s RetroNectin).
It is no trivial feat that there are currently four approved and marketed CAR-T products helping treat patients with significant unmet clinical needs. The cellular immunotherapy field is clearly not resting on its laurels, and it is truly impressive to see the scale and scope at which the various challenges are being tackled. While the approval of these treatments will be driven by the efficacy observed in robust clinical trials, it is key to stress that the often overlooked obstacles like complex manufacturing and high cost can prevent the timely translation of incredibly powerful science to real-world patient impact. Overcoming these hurdles are key to eventually bringing novel cellular immunotherapies to the masses, and while we’re not there just yet, I’m confident that we at least know where we need to direct our collective efforts.