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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This is a sobering episode that traces the history of the treatment of brain cancer – principally malignant glioma, since it is the most common diagnosis in a thankfully rare oncology indication – and how, unlike many of the indications we have discussed, the treatment options have been limited. The diagnosis of brain cancer often takes too long, partly because headaches and behavioural changes divert patient referrals to other specialities before patients end up at the door of a neurosurgeon after a CT scan. Surgical removal of tumours, chemotherapy and radiation then remained the staple of care for decades. Even the Gliadel wafer was a combination of these older interventions.

And while surgical debulking, chemo- and radiotherapy will remain in the treatment armoury for brain cancers, more recently there have been developments from biotech and pharma companies that are changing the treatment landscape. The recent approval of the BRAF, MEK and RAF kinase inhibitors that combine specific tumour-associated metabolic inhibition and the molecular genetic profile of tumours have brought modern drug discovery and development to the treatment of brain cancer. But there remain significant challenges in the form of access of new agents to tumours in the brain because of the blood-brain barrier. Even here, medicinal chemists are turning their attention to optimizing the brain penetrant potential of new molecules.

To bring us up to date, and offering much future hope, there are the clinical trials of classes of agents that have proven their worth in other oncology indications like PARP inhibitors, the PD-1 inhibitors, immune-oncology in general, and even CAR-T cellular therapies, that will hopefully add to the diversity of therapeutic options to treat brain cancer. While individual case reports are interesting, we also discuss one remarkable recently publicized combination of many current and experimental therapies that has galvanized hope for these patients.

This episode is dedicated to the patients who have sadly succumbed to brain cancer, including Jacob Whitehead and Nick Bowen and their families. Our commiserations and hopes for the future.

Companies mentioned in this episode:
Eisai, Inc., Novartis, AG, Day One Biopharmaceuticals, Servier, Medicenna Therapeutics, AnHeart Therapeutics, NeoImmuneTech, Nerviano Medical Sciences, Merck KGaA, Aveta Biomics, Moderna, Inc. Merck & Co., Inc.

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Ophthalmology has long been a fruitful area for biotechnology innovation. In highly prevalent conditions associated with ageing, such as age-related macular degeneration, or with chronic disease, such as diabetic macular oedema, vascular endothelial growth factor inhibitors have made important contributions to stabilizing vision over the past two decades. Incremental innovation has steadily improved efficacy while lowering the frequency of injections. And newer targets, such as components of the complement cascade and angiopoietin, are extending the range of therapeutic options available.

Progress in inherited retinal disease (IRD) has been slower, however. No gene therapy has gained approval in an IRD since Luxturna (voretigene neparvovec) did so in 2017. Moreover, Luxturna, which is approved for treating biallelic RPE65 mutation-associated retinal dystrophy, has not been a commercial success, while some of the bigger players have written off billions of dollars in R&D investments because of acquisitions that have failed to deliver.

Classical gene replacement approaches continue to be challenging because of the huge variety of genes associated with IRD – about 270 have been described. Developing individual gene therapies for each is not feasible with current technologies. A newer wave of ‘mutation-agnostic’ gene therapies has moved into the clinic in the last year. These do not address a specific disease-causing mutation but aim to slow the rate of vision loss by improving the metabolic status of damaged photoreceptor cells. Exon editing and cellular reprogramming are at an earlier stage of development, but could also provide ways of addressing multiple disease-associated mutations with a single therapy. The field has never been short of creative ideas – but it needs some clinical success.

Companies mentioned in this episode:
Ascidian Therapeutics, Beacon Therapeutics, Biogen, Editas Medicine, Endogena Therapeutics, Genentech, Gyroscope Therapeutics, Johnson & Johnson, MeiraGTx, Nightstar Therapeutics, Novartis, Ocugen, Ophthotech, Pfizer, Rezolute, Roche, SparingVision, Spark Therapeutics, Thrombogenics, ViGeneron

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For all the extraordinary progress we have seen in basic biological research and in the development of advanced therapies, allergy is an area that seems to be stuck and badly in need of innovation. For some, an allergy may be little worse than an irritant, but for those with severe allergies to certain foods or insect stings, it may be a matter of life and death.

The immunotherapy approaches that are still the basis of many development efforts were originally pioneered by Leonard Noon and John Freeman over a century ago. The basic concept is unchanged – the idea is to first diagnose and then desensitize the patient by exposing them to gradually increasing amounts of allergen.

An informal cottage industry of office-based allergists has developed in Europe and the US based around this idea. Companies like DBV Technologies and Aimmune Therapeutics have attempted to put the field on a more solid evidential footing by conducting randomised controlled trials, but clinical and commercial success have both been difficult to obtain.

Antibody developers long used to developing therapies for conditions such as allergic asthma and atopic dermatitis have entered the fray in more recent times. More than two decades on from its original approval, Xolair (omalizumab), an antibody that binds IgE antibodies, gained approval this year for managing multiple food allergies, and Regeneron Pharmaceuticals is in phase 3 with an antibody cocktail for managing birch allergen. But for those with severe allergies, avoidance remains the best protection. Antibody therapies can lower the risk of anaphylaxis in the event of an accidental exposure – but they can’t eliminate it.

Companies mentioned in this episode:
Aimmune Therapeutics, DBV Technologies, Genentech, Nestlé, Regeneron Pharmaceuticals, Stallergenes Greer

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A couple of years ago, PROTACs were ubiquitous. Start-ups were devising increasingly clever ways of making them, while large pharma companies were queuing up to tap into their expertise and their development programs. Proteolysis-targeting chimeras, to give them their full title, emerged as a clever and versatile way of degrading, with exquisite selectivity, disease-associated proteins that were hard to drug by conventional means.

First described over two decades ago, by Kathleen Sakamoto, Raymond Deshaies, and Craig Crews, they comprise ‘heterobifunctional’ small molecule drugs that bind a protein of interest at one end and an E3 ubiquitin ligase at the other. This triggers the sequential addition of several ubiquitin molecules, which ‘tag’ the protein for degradation in the proteasome, a key element in the cell’s waste management machinery. Over a decade later, scientists at Celgene (now Bristol Myers Squibb) discovered that their blockbuster immunomodulatory multiple myeloma drug Revlimid (lenalidomide) was in fact a prototypical PROTAC, and this set the stage for a massive influx of investment and development across the biotech industry.

PROTACs target intracellular proteins only, but several other analogous approaches have emerged in order to address extracellular proteins, membrane proteins or non-protein metabolites. These employ alternative targeting strategies either to direct a molecule of interest into other degradation pathways, involving lysosomal degradation or autophagy, for example, or to prevent it from fulfilling a function needed for the cell’s survival.

The field appears to have grown quiet of late – but it has by no means run out of steam. The early leaders – chief among them Arvinas – are now in the clinic and evaluating whether their innovative science will translate into clinical benefit for patients. Most of the initial development effort is focused on cancer and, to a lesser extent, on autoimmune disease. But if PROTACs – and their relations – can be shown to work, the clinical possibilities are very wide indeed.

Companies mentioned in this episode:
Arvinas, Avilar Therapeutics, Bayer, Biogen, Bristol Myers Squibb, C4 Therapeutics, Celgene, Cullgen, Genentech, Halda Therapeutics, Nurix Therapeutics, Frontier Medicines, Kymera Therapeutics, Millennium Pharmaceuticals, Lycia Therapeutics, Monte Rosa Therapeutics, Novartis, Nurix Therapeutics, Paq Therapeutics, Pfizer, Roche, Sanofi, Vertex Pharmaceuticals, Vividion Therapeutics

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Over 10% of the world’s population – or 850 million people – are estimated to have kidney disease, and the problem is growing rapidly. The vast majority lives in low-income or low-and-middle-income countries, and, without access to primary healthcare, may be unaware of the problem until it is too late – organ failure and early death follow. Only dialysis and organ transplant can prolong the life of patients with kidney failure, but neither is hugely scalable, particularly in low-resource settings.

Although asymptomatic until its later stages, kidney disease is easily diagnosed through urine and blood tests. In low-income countries, malnutrition, dehydration, infection and exposure to environmental toxins are important risk factors for kidney disease. In wealthy countries, kidney disease is often seen as a complication of other conditions, such as diabetes or high blood pressure. The treatments administered to patients reflect these lead-in indications – lowering blood sugar levels, lowering blood pressure and blockade of the renin-angiotensin-aldosterone system (which controls blood pressure and fluid balance) are all important interventions. The advent of newer classes, such as sodium/glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1(GLP-1) receptor agonists, and endothelin receptor antagonists have further improved the prospects of those patients who have access to them.

The cause of many cases of kidney failure remains unclear, however, although lowering inflammation and fibrosis are two additional approaches that have promise. Historically, kidney disease has not been a major focus of innovative biotechnology companies, although several large transactions in recent times indicate that that may be changing. Vertex Pharmaceuticals recently entered a $4.9 billion acquisition agreement with Alpine Immune Sciences, and Novartis acquired Chinook Therapeutics last year for $3.2 billion upfront. The focus of both deals is IgA nephropathy (or Berger’s disease), which arises from the damaging deposition of antibody complexes in the kidney.

Definitive data from large-scale phase 3 trials is still several years away. In the meantime, a recent consensus statement (Francis, A., et al., 3 Apr. 2024, Nat. Revs. Nephrol.) from several expert groups has called for the inclusion of kidney disease on the World Health Organization’s list of priority non-communicable diseases and the recognition of its varied causes and drivers in different regions and populations.

Companies mentioned in this episode:
Alpine Immune Sciences, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, Chinook Therapeutics, CSL Vifor, GSK, Novartis, Sanifit, Travere Therapeutics, Renalys Pharma, Vertex Pharmaceuticals

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