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 of clinical trials (Phase1, 2 and 3) testing the safety, efficacy or even long-terms effects of such infusion (clinical trials registry/EU). Most solid tumour indications are in the pre-clinical stage however and have a long way before being marketed.
Patient success stories (and failures)
Pivotal post-marketing analysis with Yescarta has shown robust and significant remission rates (and years gained) in older B-cell lymphoma patients who have failed two initial lines of cancer treatment. Another dataset pointed out to an astonishing three-year survival rate of 50 per cent.
Its close competitor – the only other CART therapy already running successfully in the market – Novartis Kymriah has shown increased efficacy with fewer side-effects in both paediatric and adult patients. The post-marketing follow-up trial has shown enhanced promise of CART adoption by clinicians and oncologists.
The most frequent side-effect that persists in the infused patients is cytokine release syndrome and intense inflammatory conditions that are mitigated by proper steroidal treatment. The other notable side-effect is neurotoxicity that has resulted in fatalities as well.
The long-standing effect of such infusions is currently being tested in several clinical trials.
Commercial scenario
Global CART therapy market can be divided into geography, type of antigen and cancer indication. The US dominates the market followed by Europe. Big pharma companies operating in this domain are listed below with different operations ranging from product development to expanding clinical pipeline to licensing deals and acquisitions.
Antigens (markers specific for specific cancer) are still in the nascent stage and are being tested in various pre-clinical phase especially for solid tumours. Some of the notable ones that have already made their way into clinical trials are CD19, CD22, BCMA, muc16, L1CAM.
Different cancer indications being tested are lymphoma, leukaemia, myeloma and solid cancers such as gliomas, breast, colorectal cancers (a lot of solid cancer therapy is being under pre-clinical and safety/efficacy phases).
Big players and their pipeline
Novartis – the first CART product Kymriah was approved in two cancer indications – both paediatric and adult ALL and B-cell lymphoma and is successfully been adopted by clinicians. Other trials in phase 1 and 2 are being conducted targeting mainly haematological indications.
Gilead – Kite pharma innovated Yescarta was marketed by Gilead after its buy-out. Yescarta is targeted for older patients who have relapsed lymphoma after 2 initial lines of treatment and is currently being evaluated promisingly at the post-marketing stage. Other trials at phase1/2 targeting ALL and solid tumours are also in the pipeline.
Juno Therapeutics – 11 clinical trials (Phase1/2) addressing different cancer indications including solid tumours like lung, breast, neuroblastoma and ovarian https://www.junotherapeutics.com/our-pipeline/
Celyad – currently in developing allogeneic off-the-shelf and modified CART T cells for wider distribution and cost redressal solutions. Solid tumour indications and B-cell malignancies are in the pre-clinical stage while colorectal cancer and AML are in phase 1 https://www.celyad.com/en/our-pipeline
Cellectis – Off-the-shelf CART therapy for alleviating the cost of manufacturing. Mostly phase 1 studies targeting haematological cancers.
Allogene – off-the-shelf and edited CART therapy for non-Hodgkins and myelomas mainly in clinical phase 1 stage and rest of pipeline in the pre-clinical stage. (They acquired the cell-based oncology asset from Pfizer).
Celgene (Bristol-Myers Squibb) – Several clinical trials including phase 3 for lymphomas and multiple myelomas are in the pipeline.
Bluebird – Pre-clinical and clinical-stage trials underway – the main focus is that of haematological cancer but with a specialised type of antigen marker (B cell maturation antigen).
Novartis dominates the market, followed by Kite Pharma, Inc., Juno Therapeutics, Pfizer Inc, Celgene Corporation, Cellectis, Sorrento Therapeutics, Bluebird Bio, and Immune Therapeutics. Collectively the key players ensure technology development through partnerships and licensing deals with smaller biotech firms as well as academic research centres. They also sponsor clinical trials to validate the technology – across several countries. Mergers and acquisitions abound in the immunotherapy domain – Kites CART (Yescarta) has been acquired by Gilead. Similarly, Juno Therapeutics has now been acquired by Celgene. Celgene, Gilead and Autolus are at the forefront of the industry-sponsored CART clinical trials.
Belgium-based Celyad and France-based Cellectis are two companies who are innovating on cost-effectiveness by off-the-shelf development of CART cells. This – if successfully leveraged- would benefit enormously on mitigating cost and thus effectively introduce the technology to a wider population globally.
How is it shaping up in India?
India has shown a substantial promise in immunotherapy and has many cancer hospitals and clinicians adopting immunotherapy either alone or in combination with chemotherapy. However, the field of CAR-T therapy is in pre-absorption stage and will take time and effort to reach the equilibration stage. One of the main caveats is the high price of manufacturing such cells and additionally the lack of a health insurance reimbursement system in India.
To adopt and equilibrate this technology, the following measures need to be implemented:
- Technological modifications to decrease the cost of development
- Off-the-shelf CAR-T-cells that will minimise manufacturing cost
- Install high-grade manufacturing facilities and
- Specialised training of clinicians, oncologists, nurses and technicians
- Introduction of speciality reimbursement models to meet patient affordability
This is the right stage for CART research in institutes and hospital labs whereby eminent scientists are developing the optimal platform and the best approach for CAR-T therapy. Recently, a specialised cell therapy (including CAR-T therapy)-based Immmuneel Therapeutics have been set up with the purpose of scalability and commercialisation of CAR-T therapy into Indian cancer market – it is currently testing the expansion and accessibility measures of CAR-T adoption in India. Concomitantly, research departments in IIT-Bombay and clinicians at TATA Memorial Hospital are investigating and addressing scientific advancements to the CAR-T technology to make it more suitable and accessible for Indian patients.
Prof Dr SV Chiplunkar, Director – ACTREC, Tata Memorial Centre and Current President of Immuno-Oncology Society of India feel that it is still a dream due to the following three main hurdles:
1) Infrastructure requirement – Although bone marrow transplants are routinely done here, the cell-based therapies require different infrastructural setup and expertise. There are not enough cGMP labs, although there is serious effort to establish them at few institutes and multinationals.
2) Regulatory bodies to certify these cGMP facilities for cell therapies and clinical trials for cell therapies are not in place – ICMR is in the process of developing guidelines for immune cell therapies.
3) Affordability and concomitant health insurance coverage would remain a challenging hurdle.
Dr Arun Anand, Chief Operating Officer and Dr Shashwati Basak, Senior Director, Quality from Immuneel Therapeutics also note the above challenges but at the same time feel it can be combated by adopting strategic and sustainable efforts across all three domains: technological, regulatory and commercial. There is a huge unmet need however acceptance would primarily be fostered through augmenting both efficacy and convenience. Pricing remains a detriment but even if there is a 10-fold reduction (from $450,000 to $55,000) in India, it would benefit a subset of patients: terminally ill and relapsed/recurrent and refractory to first/second line of treatment. Strategic initiatives with the Government to adopt policies and guidelines for cell-based therapy and to establish an ecosystem for CAR-T development and adoption is the main goal. To achieve this goal, Immuneel is collaborating globally across academic-industry platforms spanned across technology, manufacturing, clinical trials, and affordability.
Within 10 months of starting operations, they have developed a strong global and national network and infrastructure to achieve its mission of CAR-T therapy development, delivery, adoption and accessibility in India.
Intresting!!