Cancer CART therapy: What are the benefits and stakes?

The last decade has been termed the immunotherapy decade in the oncology-immunology sphere – thanks to the rapid and successful research and development pipeline of cutting-edge cancer therapies that are indeed showing promise in curing relapsed and refractory cancer. From pre-clinical research and approved clinical trials to actual marketed launch of these ‘super drugs’ the title is appropriately bestowed.

Amongst immunotherapies, the latest and most innovative is CART–T-cell based immunotherapy. 2017-2018 saw two big pharma companies launch two such drugs that were successful in treating refractory haematological malignancies – Novartis Kymriah (for paediatric and young adults B-cell ALL) and Gilead Yescarta (refractory non-Hodgkin lymphoma). Soon after, there have been a plethora of activities – R&D, regulatory and commercial that has globally bolstered the technological promise of this new therapy. Developing nations such as India have also been considering the efficacy and superiority of this technology – however high cost remains a challenge in the adoption of this technology (more on that later).

Technology

A chimeric antigen receptor is a synthetic protein that is developed by the fusion of extracellular antigen-recognising domains and intracellular signalling domains. These T-cells can additionally be modified by genetic engineering to augment desired immunological outcomes. Recently, gene-editing technologies such as CRISPR are also being incorporated into the design of such cells.

Steps of the therapy – Patients T-cells are harvested and genetically engineered to insert the tissue-specific marker (in this case cancer-specific marker) as well as co-stimulatory inserts (as required). Next, the cells are expanded and infused back into the patient. This whole activity takes two weeks. After infusion, the T-cells target the specific tumour, proliferate and activate killing mechanism by various effector mechanisms. 

Core advantages – Precise targeting, patients own T-cells harvested (effective auto-immunity tolerance), relatively fast time for the entire activity, robust effector mechanisms, one-time infusion as cells multiply and augment responses

Side effects – Cytokine release syndrome and neurological symptoms are the primary clinical side-effects encountered during the therapy.

Pitfalls – Selection of markers have to be very specific (a lot of research is underway to select specific markers for various cancers), high cost as several steps involved (off-the-shelf T -cells are being tested to minimise the manufacturing and transport resources). 

Cancer indications

Both KYmriah and Yescarta is CD19-based CART therapy treating B-cell ALL and non-Hodgkin lymphoma with successful clinical outcomes.

The therapy has shown challenges in combating solid tumours – this has been mainly due to the immunological micro-environment of such tumours and the relatively imprecise targeting markers of such tumour. Several studies in the pre-clinical phase are underway that are selecting specific markers for several indications such as colorectal, breast, gliomas and ovarian cancer. A few of them are being tested in Phase 1,2 clinical trials.

Regulatory approvals and current clinical trials

USA clinical trials database has 135 clinical trials (ongoing and just completed) in different phases (Phase 1,2 and 3) testing either newer cancer indications or modifications to haematological cancers (lymphomas, leukaemias and myelomas) as well as treatment monitoring over a long-term period. Many of these trials are centred on combination effects of chemotherapy and CART therapy and whether this has a better outcome than either alone. In Europe, there are 37 CART-related ongoing trials in different stages