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When the first chimeric antigen receptor T-cell (CAR-T) therapy was approved in 2017, there was a general expectation that T-cell receptor T-cell (TCR-T) therapies would follow shortly afterwards and would greatly expand the range of addressable antigens. Despite considerable efforts, CAR-T therapies are still limited to haematological cancers expressing extracellular antigens, such as CD19 or B-cell maturation antigen (BCMA).

Autologous TCR-T therapies can be engineered to target intracellular as well as extracellular peptide antigens presented on the cell surface by human leukocyte antigens (HLAs) and can be more readily used in solid tumors as well as in haematological cancers.

Progress has been slow, however, given the complexities involved in both product design and process development. A decade ago, the field grappled with the issue of toxic and sometimes fatal cross-reactions between epitopes present in proteins expressed in healthy tissue and those contained in the targeted tumor antigens. More recently, the great challenge has been to ensure that engineered TCR-T cells are healthy enough to expand and persist once transferred back into patients.

This year marks an important milestone for the field, as the FDA is due to grant – or deny – approval of Adaptimmune’s T-cell receptor (TCR) T-cell (TCR-T) therapy Afamitresgene autoleucel (afami-cel) for treating melanoma by 4 August 4.

In this episode, we trace the development of the TCR-T technology and sketch out its future possibilities with Selwyn Ho, CEO of TCR-T therapy developer Medigene.

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In 1934, Mary Walker, a pioneering Scottish physician, successfully, albeit transiently, treated a myasthenia gravis patient with physostigmine, a traditional remedy for treating poisoning with curare. She had noticed that the signs and symptoms of myasthenia gravis resembled those caused by curare, a preparation of plant alkaloids used to arm poison arrows by some indigenous peoples in Central and South America. Her clinical observations were extraordinarily accurate. At a molecular level, curare, which induces muscle paralysis, acts as a competitive inhibitor of the neurotransmitter acetylcholine by binding the nicotinic acetylcholine receptor and preventing the transmission of an action potential across the neuromuscular synapse, which would ordinarily lead to muscle contraction.

In myasthenia gravis a similar problem arises due to the presence of autoantibodies that bind to and block the nicotinic acetylcholine receptors expressed on muscle cells. (In a minority of patients, the auto-antibodies may bind to other proteins present in the neuromuscular junction, such as muscle-specific kinase or LPR4). The condition, which literally means ‘serious muscle weakness’, is highly variable. The muscles affected include those involved in controlling the movement of the eyes and eyelids, facial expression, chewing, speaking, and swallowing. Additional damage to the neuromuscular synapse develops through the activation of the complement system. Although most people who have the condition have a normal life expectancy, a minority experiences life-threatening crises, when the muscles that control breathing cannot function. They require ventilator assistance and therapeutic interventions, such as plasma exchange or intravenous immunoglobulin.

Walker’s remedy, physostigmine, a natural product isolated from a number of tropical plant species, was an early example of a cholinesterase inhibitor, which boosts levels of endogenous acetylcholine by slowing its breakdown. Cholinesterase inhibitors remain a mainstay of therapy along with immunosuppressive therapies and surgical removal of the thymus, which remains active in some patients, and which may contribute to their immune dysfunction. In more recent years, antibody-based therapies that target either complement activation or the neonatal Fc receptor (which maintains IgG antibodies, including autoantibodies, in circulation) have come to the fore. CAR-T cell therapies are also in the mix, although the data here are so far mixed. But the long tradition of innovation in treating myasthenia gravis continues.

Companies mentioned in this episode:
Ablynx, Alexion, Argenx, AstraZeneca, Cartesian Therapeutics, Harbor Biomed, Johnson & Johnson, Kyverna Therapeutics, NMD Pharma A/S, UCB

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Melanoma has been at the very centre of the cancer immunotherapy revolution over the past decade and a half. The CTLA-4 inhibitor Yervoy (ipilimumab), which gained approval in 2011, was the first agent to demonstrate a survival improvement in a phase 3 trial for metastatic melanoma. It was also the first immune checkpoint inhibitor to gain approval, and it kick-started a whole new era in cancer therapy, based on jamming the cancer’s immunosuppressive signals to enable patients’ T-cells to attack cancer cells.

The first PD-1 inhibitors followed shortly afterwards, and these proved even more active. Combinations proved even more potent again: patients on Yervoy and Opdivo (nivolumab, a PD-1 inhibitor) had median overall survival of 72 months on the CheckMate-067 trial which Bristol Myers Squibb conducted – 49% of patients treated were still alive after six and a half years, and 77% of them were no longer on treatment. The same company recently gained approval for another combination, Opdualag (relatlimab, a LAG-3 inhibitor, and the PD-1 inhibitor nivolumab), which offers similar levels of efficacy but causes less side effects. In parallel, small molecule kinase inhibitors have also proven active, in melanomas with mutations in the BRAF proto-oncogene, which leads to a cellular growth switch being turned permanently on.

Despite these advances, many patients eventually relapse, and work is ongoing to address the problem. The first tumor infiltrating lymphocyte therapy gained approval earlier this year, and others are in development. The first individualised cancer vaccine is also nearing approval. The hope is that these new therapies will help at least some relapsed patients to achieve further long-lasting remissions.

Companies & organisations mentioned in this episode:
Amgen, Biontech, Array Biopharma, Bristol Myers Squibb, Daiichi Sankyo, Evaxion Biotech, Iovance Biotherapeutics, Merck, Moderna Therapeutics, National Cancer Institute, Obsidian Therapeutics, Pfizer, Plexxikon & Regeneron Pharmaceuticals.

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