First patient receives novel in vivo gene therapy for blood cancer

A novel gene therapy approach that directly targets immune cells within a patient's body has been trialled in a B-cell cancer patient.

CAR-T therapy is a form of immunotherapy targeting cancer, where a patient's own immune cells are manipulated to help fight cancer cells. So far, this has been conducted 'ex-vivo', where white blood cells, called T-cells, are extracted from the patient's blood and edited to target specific antigens present on tumour cells and reintroduced into the patient by injection. Now, scientists at Interius BioTherapeutics in Philadelphia, Pennsylvania, have developed an 'in-vivo' approach, where immune cells are manipulated within the patient using a vector to deliver a CAR transgene directly. The in-vivo approach has now been tested in a Phase 1 clinical trial.

'This milestone marks the first time that a durable in vivo CAR therapy has been used in the clinic. INT2104 has the potential to overcome ex vivo CAR therapy challenges with a single-dose, off-the-shelf, widely accessible therapy for the treatment of B cell malignancies enabled by Interius's programmable platform,' said Dr Phil Johnson, president and CEO of Interius BioTherapeutics.

Ex-vivo CAR therapy has been widely used, and only the specific, extracted T-cells from the patient are manipulated in the laboratory using a lentiviral vector to deliver the CAR transgene (see BioNews 1231, 1195, 1172, 1131 and 904). This eliminates the risk of off-target effects, where other unwanted cells could be affected by the therapy. However, each batch of ex-vivo therapy needs to be prepared individually which is costly and can also result in significant delays for patients awaiting treatment.

The in-vivo therapy, INT2104, has been developed also using a lentiviral vector, but delivers the CAR transgene directly into a patient to target and convert both T cells and NK cells, which then specifically target B-cell cancers.

'We're creating not only CAR T cells but also CAR NK cells with a single vector,' Dr Johnson told Inside Precision Medicine. '… [this] provides a much broader population to attack the tumors – in this case, the lymphoma cells right next to where the [T and NK cells] live.'

As this therapy is not tailored to an individual's immune cells, this approach has the potential to be used across patient populations. The effectiveness of the therapy has been shown in several preclinical animal cancer models, and has now been trialled in a human patient. To date, no toxic or off target effects have been reported. However using a viral vector in vivo does pose concerns, such as activating cancer-causing oncogenes. Hence, the approach will need to be carefully monitored.

This approach may also be applicable to other diseases, such as autoimmune disorders. However, the development of this therapy is still in its early stages, with the Phase 1 clinical trial focusing on the safety of the approach. The next stage of clinical trials will focus on dose escalation and is due to begin next year.