It is becoming clear that many first generation cell therapies are limited in efficacy by the mixing of cell populations and exhaustion of cells in culture. Many widely used stem cell therapy protocols, for example, may generate significant numbers of senescent cells in the process of preparing cells for injection. Small differences in protocol and implementation may produce large differences in outcome. Injecting senescent cells along with therapeutic cells is undesirable, and in addition to being directly harmful in any significant number, the presence of senescent cells during preparation of the therapy likely negatively impacts the beneficial characteristics of the other cells.
The situation becomes more complex for cell therapies that use immune cells. The immune system is a dynamic network of shifting cell behaviors and capabilities, adaptive to circumstances. Within any broad category of immune cell, such as T cells, monocytes, and so forth, individual cells are capable of adopting a wide range of states, and changing their states and behaviors quickly in response to circumstances. It is perhaps not surprising to find that these forms of cell therapy can be optimized dramatically, given the right approach to selecting only the desired cells, or at least excluding those that are most unhelpful.
People have been cured in the clinic of advanced melanoma through treatment with their own immune cells that were harvested out of tumor tissue. The problem is, because of the way the cells are harvested, it only works in a very small number of patients. The cells of interest, called tumor-infiltrating lymphocytes (TILs), are natural immune cells that invade tumor tissue. In cell therapies used in clinics today a mixture of "exhausted" and "naïve" cells is used to treat tumors. After they are extracted from tissue, cells are grown in labs far away from the patients they were harvested from. By the time they've multiplied and are ready to be placed back in the body, many of the cells are exhausted and unable to fight, having been in the tumor for too long.
Using a new technology called microfluidic affinity targeting of infiltrating cells (MATIC), researchers can pinpoint which cells are most active through cell sorting techniques enabled with nanotechnology. Scientists used MATIC to find what the authors called the "Goldilocks population" of cells, producing dramatic results for the mice population they were looking at. Tumors in mice shrank dramatically - and in some mice disappeared completely - producing a large improvement in survival rates compared to more traditional methods of TIL recovery.
Adoptive cell therapies require the recovery and expansion of highly potent tumour-infiltrating lymphocytes (TILs). However, TILs in tumours are rare and difficult to isolate efficiently, which hinders the optimization of therapeutic potency and dose. Here we show that a configurable microfluidic device can efficiently recover potent TILs from solid tumours by leveraging specific expression levels of target cell-surface markers. The device, which is sandwiched by permanent magnets, balances magnetic forces and fluidic drag forces to sort cells labelled with magnetic nanoparticles conjugated with antibodies for the target markers.
Compared with conventional cell sorting, immunomagnetic cell sorting recovered up to 30-fold higher numbers of TILs, and the higher levels and diversity of the recovered TILs accelerated TIL expansion and enhanced their therapeutic potency. Immunomagnetic cell sorting also allowed us to identify and isolate potent TIL subpopulations, in particular TILs with moderate levels of CD39 (a marker of T-cell reactivity to tumours and T-cell exhaustion), which we found are tumour-specific, self-renewable and essential for the long-term success of adoptive cell therapies.