Cytokine release syndrome (CRS)

Afami-cel showed that T cells can be redirected against an intracellular cancer antigen, something CAR-T cannot do, and produced meaningful responses in a rare sarcoma with few options. It opens a path to TCR-T against other shared antigens and neoantigens. Restriction to one HLA type and one antigen, plus complex manufacturing, means it will help a small, defined group.

Patients with advanced synovial sarcoma, a rare cancer of young adults with few effective drugs, now have an approved cell therapy that produces responses lasting about a year in a substantial minority, if their tissue type and tumour antigen match. It proves that engineered T cells can work against a solid tumour when a good target is present, which had been elusive. It is not a cure for most, requires specialised centres, and only a minority of patients are eligible.

CARTITUDE-4 is the first randomised trial to show that a CAR-T improves survival in myeloma, and it moved cilta-cel into second-line use (FDA approval 2024). For patients whose disease returns after first-line lenalidomide, a one-off cell therapy now competes with continuous drug combinations. Capacity, cost and the need for bridging therapy still limit who actually receives it.

Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.

CD20 x CD3 bispecifics gave patients whose lymphoma has failed CAR-T, or who cannot access it, an effective off-the-shelf treatment that can be started within days. Epcoritamab and glofitamab are now standard third-line options and are moving into earlier lines and combinations. They do not yet replace CAR-T, whose remissions appear more durable.

KarMMa-3 was the first randomised evidence that CAR-T beats conventional drugs in myeloma and led to ide-cel's approval after two prior lines. It confirmed that earlier use of CAR-T produces deeper and longer remissions than in the end-stage setting. Because responses are shorter than with cilta-cel and OS was not improved, it also sharpened debate about which BCMA CAR-T to use and when.

Elranatamab confirmed that BCMA bispecifics are a class, not a one-off, and its protocol-built dose reduction after response set a precedent for lowering the immunosuppressive burden of T-cell engagers. Patients now have two approved BCMA bispecifics and one against GPRC5D (talquetamab). Choosing between them, and sequencing them with CAR-T, remains guided by availability and toxicity profile rather than head-to-head data.

Teclistamab showed that an off-the-shelf bispecific can approach CAR-T-like response rates in late myeloma, giving patients who cannot wait for or access cell therapy a real option. It also exposed the price: prolonged T-cell engagement causes profound immunosuppression, so infection prophylaxis and immunoglobulin replacement are now routine. Less frequent dosing after response is being adopted to reduce this burden.

TRANSFORM confirmed ZUMA-7's conclusion with a different CD19 CAR-T and a more permissive design that allowed bridging chemotherapy, making the results closer to real-world practice. Liso-cel's low toxicity makes it attractive for older or frailer patients and for outpatient delivery. Together the two trials made CAR-T the standard second-line therapy for early-relapsing aggressive lymphoma.

ZUMA-7 rewrote second-line treatment for aggressive lymphoma: patients whose disease returns within a year of R-CHOP should be offered CAR-T rather than salvage chemotherapy and transplant. It is also one of the few cell-therapy trials to show an overall survival benefit despite crossover. Patients relapsing later than 12 months were not studied and transplant remains standard for them if chemosensitive.

Checkpoint inhibitors are now given to hundreds of thousands of patients a year, many in community clinics and emergency departments, so a common, explicit playbook for their autoimmune side effects saves lives. The guideline standardised when to stop, when to give steroids and when to escalate, and made multidisciplinary toxicity teams routine. It does not remove the judgement needed for rare events or for patients whose cancer is responding.

CARTITUDE-1 showed that a single CAR-T infusion can put late-stage myeloma into deep, multi-year remission, leading to FDA approval of cilta-cel in 2022 for heavily pretreated disease. It set the efficacy bar for BCMA-directed therapy and motivated moving CAR-T earlier (CARTITUDE-4). Late neurological toxicity and secondary malignancies remain the safety questions.

The UCART19 report was the first clinical evidence that a universal, pre-manufactured CAR-T made from a donor can work, avoiding the weeks of autologous manufacturing and the problem of patients whose own T cells are too damaged. It set the template for later allogeneic programmes (including cemacabtagene autoleucel in the ALPHA studies) and for in vivo CAR generation. Short persistence and the need for deep lymphodepletion remain the central weaknesses.

ZUMA-2 gave patients with BTK-inhibitor-refractory mantle cell lymphoma, who previously had a median survival under a year, a therapy with durable remissions in a substantial fraction. Brexu-cel is now standard after BTK inhibitor failure and CAR-T is being tested earlier in the disease. Neurotoxicity rates are higher than in other lymphoma CAR-T trials.

JULIET, with ZUMA-1, showed that CAR-T could rescue a substantial minority of adults with chemotherapy-refractory lymphoma and that complete responders often stay in remission. The lower toxicity of a 4-1BB construct and the option of bridging therapy made it usable in a broader population. The high drop-out between enrolment and infusion remains a lesson about turnaround time.

ELIANA turned CAR-T from a single-centre experiment into a licensed product and created the regulatory and logistical template every later cell therapy has followed. For children with refractory leukaemia it offers a chance of durable remission without transplant. The trial also exposed the gaps: manufacturing failures, patients dying while waiting, and roughly half relapsing within a few years.

ZUMA-1 showed that CAR-T can cure a meaningful fraction of adults whose aggressive lymphoma no longer responds to chemotherapy, a group with a historical median survival of about six months (SCHOLAR-1). Axi-cel became the first CAR-T approved for lymphoma and later the first to beat standard second-line therapy in ZUMA-7. The comparatively high neurotoxicity of CD28-costimulated products was also first characterised here.

This paper is the proof-of-concept for a living drug: a single infusion of a patient's own engineered T cells could eradicate leukaemia that had survived chemotherapy, transplant and antibody therapy. It defined cytokine release syndrome and its antidote, tocilizumab, and revealed antigen-loss relapse. It led directly to the first approved gene-modified cell therapy three years later.