Central Research

Novel Therapeutic Modalities: Where to innovate?

CAR-T Immunotherapies. Is it possible to design a more complex product?

In recent years, the use of CAR-T cell and related immunotherapies based on geneticallymanipulated immune cells have shown a remarkable success, not only in the treatment of haematological cancers, but also as an effective weapon against solid tumours. Despite the clinical efficacy shown by these treatments, there are still quite a few aspects that remain problematic, including the ‘persistence’ of the therapeutic effect, the incidence of severe undesirable effects (chiefly cytokine release syndrome), linked to a large degree to their own pharmacological effect, and finally the fact that most of these therapies are ‘autologous’, which complicates tremendously not only the manufacturing, but also the eligibility of patients that could benefit from these treatments.

This has forced to put a great emphasis in designing the right therapeutic cell that can elicit an optimal clinical response in the patient, but also that can be manufactured with relative ease.

On one hand, requirements of large number of cells puts extraordinary demands and constraints in the manufacturing process, but also in the original biological material obtained from patient apheresis. After all, at this point in their clinical journey these patients are severely ill and therefore, not in an optimal condition to provide the required number and quality of immune cells to manufacture the final immunotherapy product.

So, clearly, in the future the design of these type of therapies will need to address the nature

of the active ingredient or API itself, but also whether a ‘universal’ or off-the-shelf form might be better suited to treat these patients. Indeed, a potential avenue explored by a few developers is pursuing the development of ‘off-the-shelf’ immunotherapies that could be used to treat virtually any patient.

On the positive side, this could perhaps help reducing the substantial development and manufacturing costs associated with these innovative therapies, largely linked to the ‘one-patient one-batch’ conundrum and the use of still inadequate platforms to address effectively process integration and automa-tion in such therapies [1].

Furthermore, immediate availability would prevent disease progression that occurs in autologous therapies during the manufacturing process from apheresis to cell transduction, expansion, batch release and patient administration, which can take several weeks.

This raises a significant risk that patients could die before their treatment is ready. However, on the negative side, such a ‘universal’ approach for immunotherapy would require the development of cells that are recognised as ‘own’ by virtually any patient, or rather cells that will not trigger rejection (allorejection) or, even worse, graft vs host disease (GvHD) responses which could be potentially fatal to the patient [2].

Some of these risks can be minimised by engineering immune cells by gene editing technologies to eliminate the expression of T-cell receptors (TCRs) or human leukocyte antigens (HLA) / histocompatibility antigens in the product. Several other alternatives are being actively developed, for example CAR-NK cells, that maintain their efficacy against the cancer cells, whilst reducing the incidence of GvHD and allorejection [3].

Moving away from the ‘active ingredient’ itself, the process of manufacturing this type of therapeutics could not be more complex. It is in fact ‘a process within a process within a process’, even if we leave aside for a moment the constraints imposed by factors such as patient personalisation, perishability of product, and complex demands in terms of chain of custody. There are indeed very complex manufacturing processes and supply chains in other industries (automotive, aeronautics, electronics, even in food), but they succeed by relying on a tight control over the design specifications of the final product.

This means, successfully controlling the quality of components and assembly / production of the final product within a very narrow range of set specifications, and by designing compatibility and interoperability of components applicable to a multitude of product configurations.

Unfortunately, none of this is present in the design and manufacture of this type of therapeutics (and perhaps in the pharmaceutical industry as a whole).

Nucleic acid therapeutics. Delivery remains a key challenge

One of the many attractive aspects of nucleic acid therapeutics is the promise of a relative simplicity of manufacture compared to other modalities, such as proteins. In fact, some have suggested that nucleic acids (particularly mRNA vaccines) could deliver the promise of true personalised medicine. However, several challenges remain for such an ‘ideal’ manufacturing process.

One of the problems with RNA therapeutics is that mammalian organisms have evolved a complex suite of responses to avoid infection by pathogens, as a result, RNA is effective in eliciting a variety of immune responses that ultimately aim to degrade a potentially infective organism as well as preventing entry into cells or even killing cells infected by this foreign genetic material.

Dose control is a potentially big challenge compared to biopharmaceuticals. This is largely linked to another shortcoming, which it is the delivery of mRNA, its stability in circulation, uptake by target cells (and stability inside cells) and translation potential.

This is perhaps why, most of the products registered and in development are vaccines. Immune activation by vaccines requires considerably lower amounts of product compared to other biopharmaceuticals, like monoclonal antibodies, which usually require large doses (up to 5-10g/Kg) to be effective.

Corollary: Can it be made? Manufacturing at the crossroads of innovation

Some see all the issues mentioned above as an inevitable evil that one must face (fortune favours the brave), however, as I have been trying to present here, there is clearly a lot of mileage in investing time and resources in addressing at least some of these issues, both as a community (academic research as well as industry), but also as part of the development efforts of individual therapeutic entities, bringing together discovery (design) and development (including manufacturing) into a coordinated effort.

Designing the product for manufacturing and designing manufacturing processes for product success are paramount in ensuring the sustainability of drug development endeavours and the affordability and accessibility of medicines to patients, and it sits at the foundation of the QbD philosophy. In this line of though some aspects need also to be considered, for example supply chain security. Unfortunately, it still occurs that products can be discontinued because manufacturing becomes cost-prohibitive for patients and health care providers.

So new / alternative manufacturing concepts and paradigms are needed to be considered, for example just-intime manufacturing, on-demand manufacturing, decentralised manufacturing, or manufacturing at point-of-care. Clearly most, if not all, of such concepts are ill at ease with the praxis currently favoured in the industry. However, it is not too far-fetched to envisage a future where medicine accessibility (and affordability) would require dramatic changes in how therapeutic treatments are produced and distributed.

If we look at the latter (manufacturing at pointof-care) proximity to patient is becoming a critical aspect for some therapies in development, particularly those involving living therapeutics, often with a limited shelf-life. Here supply chain logistics, full traceability and chain of custody become essential. Perhaps integration of new technologies, such as blockchain (secure encrypted ledger) could become a saviour to guarantee traceability, compliance whilst maintaining full confidentiality.

So, in conclusion, concerted efforts in the under- standing of active ingredients and their mode of action as well as in the design of the therapeutic product including APIs and delivery platforms (formulation, dosage form and device), will help developing medicines that are both effective and affordable to those that need them the most.

Jesus Zurdo, PhD

Global Head Cell, Gene Therapy & Bioproduction at Horizon Discovery