Genetically engineered T cells derived from patients have been developed to recognise and destroy human-derived bladder tumours in mice. The team was able to control these tumours by delivering treatment directly via catheter, minimising side effects, and hope to translate this work into an effective treatment in the clinic.
As one of the most common cancers worldwide, bladder cancer treatment typically involves surgical tumour removal followed by chemotherapy. However, some cancers are resistant to chemotherapy which means the patient’s bladder must be removed, resulting in significant complications. Researchers searching for bladder-sparing cancer therapies are now looking to immunotherapies like chimeric antigen receptor T cells (CAR-T).
While intravenous CAR-T therapy has been game-changing for treating blood cancers, solid tumours account for 80-90% of adult cancers. Adapting CAR-T cell therapy for solid tumours has proven difficult, with problems balancing potency and toxicity. Many solid tumours, such as bladder cancer, have proven particularly difficult-to-reach with intravenous CAR-T therapy as scar-like tissue can block infiltration.
In this study, the team demonstrated the first CAR-T cell therapy in mice that targets bladder cancer antigens while avoiding healthy cells. By identifying a target that is overexpressed in bladder cancer, MUC16, but present at minimal levels in healthy tissues, the team created a CAR system that should be highly effective with fewer side effects.
‘Initially, we used an antibody which is a binder to MUC16, however we realised that entity was cleaved and therefore not expressed in bladder cancer,’ explains Taha Merghoub, co-lead on the study and deputy director of the Meyer Cancer Centre, US. ‘So, we went back to the drawing board and, instead of using an antibody, we use the portion of mesothelin [cell surface protein] that binds to tandem-repeat domains on MUC16.’
Using recombinant DNA technology, the team chemically stitched a DNA fragment that corresponds to the mesothelin protein to a peptide backbone. Using a retroviral vector, they introduced this CAR system into human T cells. By adding a ‘co-stimulatory domain’ to boosts CAR-T cell proliferation, the researchers improved potency.
The team then validated the delivery system on two other cancer targets with direct injection into the bladder. Merghoub said this provided an ‘elegant’ way of showing the principle applies beyond MUC16 for treating cancers, and this direct delivery avoided harm to healthy cells by limiting leakage of the potent CAR-T cells into other tissues. Mice treated with these mesothelin-directed CAR-T cells exhibited ‘significantly reduced tumour burden’, compared with those that received control T cells without the targeting moiety.
Oladapo Yeku, a clinician at Massachusetts General Hospital, US, who is investigating MUC16 for ovarian cancer, says this work contributes to growing recognition that ‘where and how we deliver CAR-T cells really matters’. It also adds to the ‘piling evidence’ that direct delivery and targeting tailored to tumour type is incredibly important.
Lab to patient
Yeku says he sees this as a ‘very big shift’ in solid tumour treatment, towards more precise therapies with fewer side effects. However, he adds that there’s a ‘big gap’ between preclinical studies and clinical trials. He says that once this reaches human trials there will be ‘no shortage of patients willing to try this therapy, especially given the strength of the preclinical data’.
This comes as CARsgen Therapeutics received approval in China for its new CAR-T cell therapy for advanced gastric and gastroesophageal cancers. While pre-clinical research in solid tumours in the last decade has grown, the approval of CARsgen’s satri-cel (satricabtagene autoleucel) is a first for the field.
John Maher, head of the CAR mechanics group at King’s College London, UK, says that while CAR-T has been ‘transformative’ in blood cancers, progress in solid tumours is incremental as they are a ‘completely different kettle of fish’. Maher says that while satricabtagene has not yet reached the efficacy of CAR-T therapies in blood cancers, it’s one of the most encouraging developments for solid tumours.
Meanwhile, he says that this research still has a lot of obstacles to overcome to move from pre-clinical to treating patients. ‘We’re all very good curing mice, but the acid test is what’s happening in the clinic, with human patient.’ Maher says that, as CAR-T therapies are ‘incredibly complex, expensive’ drugs, clinical trial costs remains one of the biggest challenges for novel therapies. He also foresees challenges going from preclinical tumour-specific CAR therapies to metastatic systems. Yeku is also keen to see metastatic models, saying that while this could be great for patients to avoid the ‘life-changing surgery’ of removing the bladder, more options are needed for patients whose cancer has spread.
Merghoub is looking to move into clinical trials soon and the team is searching for other antigens to co-target to increase specificity, reduce side effects and optimise potency. He adds that by further promoting the patient’s own T cell response, metastasis could be prevented in cancers – if they’re caught early enough.
‘Maybe it’s naive but I think [in clinical trials] there will be a degree of tumour killing that will call in the patient’s own T cells and then we can think “If these are coming in, how do you boost them?” The cool thing about these endogenous T cells is they are like a Swiss army knife and can recognise tumours from different aspects and reduce relapse.’
