What types of cancer can be treated with cell therapy?
To date, cell therapy has had the best results in treating very specific types of a blood cancer called B-cell lymphoma. These cell therapies have largely been autologous CAR-T therapies, whose starting material consists of patients’ own immune cells. In this process, a patient’s T cells are infected with a virus to induce them to express a protein called a chimeric antigen receptor (CAR) that allows the cells to more effectively target the patient’s cancer cells.
Traditionally, the best results have been achieved using CARs that target CD19, a protein present on B cells, which is why B-cell lymphoma has been a primary target of cell therapies to date. While this initial discovery generated significant interest in finding targets other than CD19 to similarly treat cancer, the process has taken longer and been more difficult than anticipated. It is possible that other cancer types will require a fundamentally different approach to cell therapy.
What role do cell therapies play in improving long-term outcomes for cancer patients?
Using cells to treat cancer is a revolutionary method compared to how cancer has been treated for decades, and cell therapies play an incredibly important role in improving long-term outcomes for some cancer patients.
The main ways of treating cancer include: surgery, in the case of solid tumours; chemotherapy, which essentially aims to poison and destroy cancer cells before too much harm is done to healthy cells; and radiation, which uses targeted beams of intense energy to kill as many of the cancer cells as possible. These traditional techniques, however, can also damage healthy cells and tissues, which are important for the patient to maintain for recovery.
The body naturally fights off cancer or precancerous lesions through the synergistic effort of many cell types in the immune system. As part of ongoing surveillance, the immune system identifies cells that may become cancerous and proactively destroys them before they have the chance to become malignant and impact a person’s health. Cells do this naturally through complex mechanisms that help them distinguish cancerous and precancerous cells from healthy cells, and then target those cells for removal in coordination with other immune cells.
Cell therapy takes cells and engineers them to target and fight cancer, enhancing the body’s own natural resources. This offers the potential to treat many types of cancer and achieve complete remission.
How has research using cell therapies to treat cancer improved in the last decade?
It has improved dramatically. The success of autologous CAR T-cell therapies, the first generation of cell therapies to treat cancer, was the result of many years of work understanding how to design CARs and introduce them to cells. These methods of manufacturing cell therapies had to be invented from scratch and be reproducible and consistent.
Over the last decade, we have made great strides in the development of next-generation cell therapies to treat cancer, most notably through the use of allogeneic cell sources. Instead of having to take a patient’s own cells and engineer them, as in the case of autologous cell therapies, allogeneic cell therapies are now being made from cells donated by healthy individuals. This material can be collected in advance and serves as the starting point for allogeneic CAR-T therapies that are currently in late-stage clinical development. These therapies have the potential to offer better outcomes for patients because they are off the shelf. These kinds of treatments would be available and ready to be administered immediately following diagnosis, so patients do not need to wait for autologous therapies to be manufactured from their own cells.
Induced pluripotent stem (iPS) cells are emerging as a cell source of interest. In manufacturing iPS cell-derived cell therapies, there is only one donor, eliminating the need to collect cells from multiple donors repeatedly and having to pool and characterise that material to ensure it’s consistent and meets appropriate specifications. With iPS cell-derived cell therapies, there is a master cell bank created of engineered, highly characterised pluripotent stem cells that are then used to differentiate into the desired immune cell.
One of the advantages of iPS cells is that they can differentiate into immune cell types aside from T cells, which may also be useful for treating cancer. These cell types include natural killer (NK) cells, other lymphoid cell types, different kinds of T cells such as gamma-delta T cells, and myeloid cell types such as macrophages, which have an innate ability to infiltrate solid tumours and the tumour microenvironment. These cell therapies could increase the types of cancers that can be treated, including solid tumours for the first time, and broaden the patient populations that could benefit.
How have positive results from clinical trials impacted the development of emerging cell technologies?
Clinical trials are critical to the development of cell-based technologies. While preclinical work is certainly informative and can give insights into safety and efficacy, ultimately one can only learn if new cell-based technologies are going to be safe and effective through clinical trials featuring human subjects.
The successes of first-generation cancer cell therapies have benefited emerging therapies enormously in terms of how best to assess clinical efficacy and establish consistent manufacturing practices. First-generation cancer cell therapies have also helped establish the regulatory framework necessary to develop and ultimately give patients access to these kinds of therapies. Regulatory authorities have had to thoroughly learn all about cell-based therapies – how they’re manufactured and characterised, as well as stability and batch-to-batch consistency requirements.
These are very different medicines from traditional drug products such as small molecules or biologics. In the case of a cell-based therapy, the drug is alive, consisting of a living cell that has to be manufactured consistently and at scale and characterised in a way that ensures confidence in its safety and efficacy. Having that regulatory framework firmly in place through the approval of first-generation cell therapies to treat cancer has paved the way for next-generation cell therapies.
What are the benefits of a multi-cell type therapeutic approach for solid tumour targeting?
While first-generation cell therapies to treat cancer have demonstrated success in a limited number of blood cancers, solid tumours have continued to remain refractory to those kinds of approaches. One of the challenges with solid tumours is the tumour microenvironment, which is incredibly hostile to cells and very difficult for immune cells to infiltrate.
However, there are some cell types, most notably macrophages, that are naturally adept at overcoming the molecular cues of the tumour microenvironment and infiltrating solid tumours. When analysing a solid tumour, one will often find that it is full of the patient’s own macrophages that have infiltrated the tumour and are trying to resolve and destroy it. But macrophages alone are rarely able to completely eliminate a solid tumour once it’s established. That is where the concept of a multi-cell type therapeutic approach comes into play; we can take advantage of the ability of one type of cell (eg, macrophages) to infiltrate a solid tumour in combination with another type of cell (eg, lymphoid cells such as T cells and NK cells) that is very adept at killing cancer cells. We can engineer these two cell types to work together, forming a multi-cell type therapeutic that can effectively infiltrate the solid tumour and then destroy it. More specifically, we can engineer macrophages to secrete cytokines that will recruit lymphoid cells such as T cells and NK cells to the site of the solid tumour. Once those cells are recruited, they can kill the cancer cells and eventually destroy the solid tumour itself. This is a novel method that is now being explored for the first time.
How can this approach help inform the development of new cancer therapies?
This multi-cell type therapy approach, in addition to offering the potential to directly address solid tumours for the first time, will invariably teach us a lot about how these kinds of cells work together and interact with cancer cells and the tumour microenvironment. This knowledge will be invaluable for the development of other, even more sophisticated, engineered multi-cell type therapeutics to treat different kinds of cancer.
