Training immune cells to catch up with cancer

Cancer treatments have come a long way since surgery was the only option. Next came radiotherapy and chemotherapy, where radiation and cytotoxic agents respectively were used to indiscriminately kill both healthy and cancerous cells. Then came small molecule drugs, which targeted specific molecular changes associated with cancer.

In recent years, antibodies have come to the fore as a treatment option that promises to be even more selective in targeting cancer.

“Now we have moved on to cell therapies where our weapons against cancer are living things,” explains Won Seog Kim, director of the CAR T and Cell Therapy Center at Samsung Comprehensive Cancer Center (SCCC) in Seoul, the first hospital in South Korea to offer chimeric antigen receptor (CAR)-T-cell therapy in 2021. “In particular, antibody therapies such as CAR T cells, which are able to home in on cancer cell surface proteins, have been very successful at treating notoriously hard-to-target blood cancers like lymphoma and leukaemia.”

CAR T cells have also been remarkably effective at treating advanced cancers and typically require fewer treatments than other standard drugs, adds Kim.

Harnessing immune cells

CAR-T treatments begin by taking some of the patient’s own T cells. T cells are part of the body’s immune system and are involved in detecting and destroying infected or cancerous cells.

Each patient’s T cells are then engineered to produce CARs on their cell surface, in effect giving them a homing mechanism to locate specific proteins found on cancer cells known as antigens. The newly modified CAR T cells are then multiplied in the lab before being infused back into the patient. If all goes well, the CAR T cells attack cancerous cells while leaving healthy cells untouched, with some eventually becoming long-lived memory cells that keep the cancer at bay for years.

However, there are a number of things that could go wrong. One of the key risks of CAR-T therapy is cytokine release syndrome, where the immune system has an overly strong response to the infused CAR T cells. Another risk is immune effector cell associated neurotoxicity, which causes side effects ranging from temporary confusion to a life-threatening build-up of fluid in the brain.

Such risks are known and can be managed if closely monitored, says Kim. “We treat more than 100 patients a year with a very low rate of intensive care unit admission, largely thanks to our multidisciplinary team of doctors and nurses, including infectious disease specialists, haematologists, neurologists and emergency care personnel,” he explains. “Functionally, our needs are like those of a small hospital, which is one reason we put together the CAR T and Cell Therapy Center.”

The refining stage

Since 2017, six CAR-T-cell therapies have been approved by the US Food and Drug Administration and many more are being developed, reflecting the great promise of the approach. Yet CAR-T-cell therapy is no magic bullet; not all patients respond to CAR-T therapy and it has only been approved in some countries for blood cancers thus far.

Furthermore, bespoke approaches to developing CAR T cells typically take too long, requiring one to two months to multiply each patient’s cells in sufficient numbers (see end box for more about SCCC’s very rapid, personalized cancer treatments). The alternative is allogenic CAR T cells, where donor engineered cells are designed to be used off-the-shelf rather than customized to each patient.

To enhance the cancer-killing abilities of the latter, Kim is currently investigating the use of small RNA constructs that reduce the expression of immune checkpoint inhibitors, which slow down the efficacy of CAR T cells.

Jeeyun Lee, director of the Precision Cancer Therapeutics Center at Samsung Comprehensive Cancer Center, is also working with Kim to expand various types of T-cell therapies to solid cancer patients, based on data from an integrative sequencing, biomarker, and clinical database system.

Understanding and measuring biomarkers will be important when it comes to assessing novel therapies for cancers such as treatment-resistant solid tumours, says Lee. These new therapies could include bispecific immunotherapies, which can target two different antibodies, and/or engineered cell therapies, which reintroduce improved immune cells to fight cancers, for example, according to both Lee and Kim.

“In the past few years, we’ve been working very hard to thoroughly characterize cancers; on the one hand studying treatments that can apply to all cancer patients and on the other hand, going beyond understanding individual patients to understanding different parts of a tumour at a single cell level,” she explains. “Precision medicine is already happening, but the future of cancer therapy is going to be even more detailed and fine-grained.”