What is cellular therapy? Is it the same as adoptive cell therapy?

What is cellular immunotherapy? Cellular therapy is a type of immunotherapy, but what differentiates cellular therapy from pure immunotherapy or some other types of immunotherapy is that some immunotherapies like checkpoint inhibitors are simply giving chemical compounds that activate our own immune system. Cellular therapies can use drugs like this, but they don't have to. But their mainstay is to actually use cells themselves to help fight the cancer. So either collecting a patient's own cells, revving them up and putting them back in, much in the same way we do with CAR T cells. But there are other what we call off the shelf cellular products or cellular therapies. And that's where we take cells that have already been engineered potentially from another donor or potentially from a cell line. And we can infuse those cells themselves into the person and have those cells directly attack the immune system. So CAR T therapy kind of straddles both. It's an immune therapy, but it's also a cellular therapy. So there's a lot of overlap between the different technologies. Cellular immunotherapy is a form of therapy whereby we take a patient's immune cells, typically their T cells, and then activate them, expand them, and in some cases genetically modify them to be able to better recognize and attack the patients on myeloma when those cells are given back to the patient after conditioning therapy or after autologous stem cell transplantation. What does adoptive cell therapy mean? That term generally refers to the process of transferring T cells or immune cells from outside the body into the patient. Just a general term that refers to the infusion or transfer of immune cells into the body, whether these are potentially immune cells that come from the patient and that are activated, expanded, or genetically modified in the laboratory, and then returned to the patient, or whether these are off-the-shelf cell therapies that come from a third-party donor and that are engineered or manufactured to be able to recognize and attack myeloma. All of those qualify as adoptive T cell or immune cell therapy. We have immune therapy, which is the other name for, for example, CAR-Ts and natural color T cells, where you actually train those cells to go after the plasma cell and fight it. Auto-transplants are really not, although they are cellular therapy in the sense that we're using cells, the purpose of those cells are actually not to fight the cancer cells. In patients where we do autologous transplants or transplants that we collect the patient's own immune system cells to give back, the purpose is not to attack the cancer with those cells. The purpose is that it allows us to give high doses of that alkylator therapy melphalan to give us enough that we wipe out even the healthy cells in the marrow. And for an autologous transplant, we infuse the original stem cells back in, not to fight off the cancer, but to fill in the gaps from the normal cells that we killed with the melphalan. Allergenic stem cell transplant or donor transplants are actually the archetypical type of cellular therapy. In this case, we give people chemotherapy to reduce their immune system so that they don't reject a new immune system that we put in. The role here is that in allergenic stem cell transplants, we understand that some of the best cancer fighters in the world are our own immune system. Unfortunately, everybody makes cancer cells 24 hours a day. Some people develop cancer because those mechanisms fall down at some level. But if you wipe away someone's immune system and give them a healthy immune system, including those cells from a donor, that intact immune system may be enough to wipe out the cancer cells that are still there. So allogeneic transplants are definitely a type of cellular immune therapy. So cellular immunotherapy in myeloma right now, the biggest impact has been with BCMA CAR T cells. And what we're seeing is in heavily pretreated patients, we're seeing very nice and deep responses. What I think is still unclear is what the durability of the overall response is, which contrasts very sharply, for example, with acute lymphoblastic leukemia in children and diffuse larcell lymphoma, where patients that achieve a complete remission appear to have durable responses. It's not clear at this point how durable the responses with BCMA CAR T cells are in myeloma. What are some cellular immunotherapies being used in myeloma, and when should they be used? So there's the role of cellular immunotherapy for myeloma is still under development, but there have been some very exciting advances in that field. At the University of Maryland, we pioneered a type of gene-modified T cell therapy for myeloma using T cells that were engineered to express a high affinity T cell receptor for a surface protein called NYESA1, which is a cancer testis antigen that is expressed frequently in patients with advanced and refractory forms of myeloma. And these redirected T cells were able to engraft into patients, proliferate traffic to the bone marrow, and in some cases help to attack and kill their myeloma cells. And these cells were, these gene-modified T cells were also quite safe and did not seem to have any significant off tumor effects. There is also several CAR T products that are under development for myeloma. These are genetically modified T cells that instead of expressing a T cell receptor on the surface express a CAR, which stands for chimeric antigen receptor, which is sort of a freak of nature where there is an antibody on the outside and T cell signaling domains on the inside. But once these CARs engage with myeloma cells, they become activated and induce proliferation expansion of the T cells, which then can go about killing the myeloma cells. And these therapies also look very promising, inducing a high proportion of responses, some of which appear to be durable, long lasting. The best place or best opportunity to give these cells is still being worked out. It does seem that CAR T cells and TCR T cells, T cell receptor T cells, work better when they are given after strong preparative chemotherapy, called conditioning therapy. And it may even be that the best preparative therapy to use is actually transplant to give patients high dose chemotherapy, get the myeloma down to a low level, and also create a milieu or an environment in the patient that is most conducive for graftment expansion and activation of these genetically engineered T cells, whether it be TCR T cells or CAR T cells. So it may be that the best time to give them may be actually very soon after high dose chemotherapy in autologous stem cell transplantation.