Immunotherapies have revolutionized the way we treat cancer by amping up a person’s own immune system to help fight this disease. Dr. Josh Hill, a physician-scientist in the Vaccine and Infectious Disease and Clinical Research Divisions at Fred Hutch, wondered how these therapies might affect our immune system in other ways, for example if the immune system can fight off infections that it had previously built immunity to. To understand whether these immune-targeting treatments might “reset” the body’s immunity or not, he started building a cohort of patients being treated with chimeric antigen receptor T cell (CARTx) therapies which supercharge a patient’s T cells to fight off cancer. Here, the T cells are instructed to attack all cells with a specific protein on their cell surface- for leukemia and lymphoma patients, these cancer cells have a marker called CD19, while multiple myeloma cancer cells have the marker BCMA. However, other normal immune cells also share these markers and, as a consequence, both of these targeted treatments destroy specific types of healthy immune cells alongside the cancer cells. Specifically, CD19-targeting CARTx therapies target most B cells, while BCMA-targeted therapies deplete plasma cells- a B cell subtype that lack the CD19 marker. Importantly, B cells are responsible for making antibodies, so having patients with certain antibody-making B cells depleted would allow Dr. Hill to investigate specific immune consequences of targeting each of these immune cell classes. As Dr. Hill was building a cohort of patients receiving these therapies, where his team would analyze patient blood samples before and after CARTx treatment to analyze antibodies present, autoimmune researcher Dr. Shaun Jackson at Seattle Children’s Research Institute enters the scene. Dr. Jackson thought these blood samples might be pretty useful to investigate all antibodies more broadly, including autoantibodies which recognize “self” from “non-self”. While Hill is still striving to understand how these immunotherapies affect a patient’s ability to fight off infections, he teamed up with Jackson when they realized they could focus on a specific type of autoantibody, to potentially uncover what cells are responsible for organ transplant rejection.
Yes, we are bouncing around a bunch of immune cells in this story, but hang tight, it’s all about to come together. Anti-HLA antibodies are a major reason for organ transplant rejection, however it’s not clear exactly which B cells are responsible for making them. Hill explains that these HLA antibodies are “fundamental proteins that help distinguish between self and non-self in the innate immune system to help us not attack our self”. Each person has many inherited HLA markers and these are the markers used to identify a good match for bone marrow transplant donors. But when the immune system sees some type of cell that is foreign to their body, they might start to produce antibodies against these HLA markers, or anti-HLA antibodies. This most commonly occurs through receiving a blood transfusion or during pregnancy. In their recent study published in American Journal of Transplantation, Hill et al. leveraged these CD19- and BCMA-CARTx immunotherapies to ask if targeting either immune cell type might deplete anti-HLA antibodies for those patients who originally presented with high levels of these antibodies. Through investigating changes in anti-HLA antibodies in these two CARTx patient groups, the researchers hoped to “understand where these HLA antibodies are coming from and identify the cell types we need to be targeting to improve organ transplant outcomes,” Hill stated.
“We hypothesized that plasma cells are most likely where these pathogenic antibodies are coming from,” Hill remarked, and thought “let’s take a shot in the dark and see if we can screen people receiving CD19-CARTx or BCMA-CARTx treatment to see if anyone has HLA antibodies.” The researchers first analyzed the blood of patients prior to CARTx treatment and asked if any of the patients had HLA antibodies. Excitingly, they found four patients receiving CD19-targeting therapy and one receiving BCMA therapy. The researchers then focused on this subset of patients and asked “did this treatment eliminate these antibodies?” Hill explained. While they weren’t able to obtain a post-treatment blood sample for the BCMA-treated patient, which is the patient where they had hoped to see an elimination or reduction in these antibody levels, they were able to analyze the blood of the four patients in the CD19-CARTx group. In line with their hypothesis, Hill et al. found that CD19 CARTx treatment had no impact on antibody levels, “there was no movement or dip [in the amount of anti-HLA antibodies present], not even a little!” An important difference in these two groups is that there were fewer BCMA patients overall with high anti-HLA antibodies. Hill speculates “it is possible that this BCMA group already had previous treatments that could play a role in depleting the HLA antibody-expressing plasma cells.” Without studying this BCMA group, the lack of effect in the CD19-targeted group provides only indirect evidence, nonetheless this is an extremely important finding that supports the hypothesis that CD19-targeted depletion is not an effective strategy that would improve organ transplantation outcomes.
Investigating HLA antibody levels in patients with B cell-depleting cancer immunotherapies as a way to find new treatment strategies to improve organ transplantation outcomes is certainly some out of the box thinking. Because of this orthogonal approach, Hill noted that this was “certainly the most unique project I’ve gotten to work on.” Ultimately this work highlights the possibility of how using targeted depletion of specific cell types may increase outcomes for solid organ transplantation. This work also suggests that these types of therapies could potentially be used for treatment of auto-immune disease. Hill stated that this research demonstrates “the power of where we’re going with precision medicine,” as these antibody-based therapeutic strategies “can be leveraged to tackle a whole host of illnesses outside of cancer.” Moving forward, Hill is asking “how can we leverage these therapies to think more broadly?” To understand how these therapies alter antibody levels more generally, Hill is collaborating with researchers at UCSF and Stanford to use “high throughput tests that allow us to look at a wide range of auto-antibodies.”
This work was supported by the National Institutes of Health and the National Cancer Institute.
UW/Fred Hutch/ Seattle Children’s Cancer Consortium Joshua Hill, Damian Green, David Maloney, Rebecca Gardner and Christopher Blosser members contributed to this work.
Hill JA, Kiem ES, Bhatti A, Liu W, Keane-Candib J, Fitzpatrick KS, Boonyaratanakornkit J, Gardner RA, Green DJ, Maloney DG, Turtle CJ, Smith JM, Gimferrer I, Blosser CD, Jackson SW. Anti-HLA antibodies in recipients of CD19 versus BCMA-targeted CAR T-cell therapy. Am J Transplant. 2023 Mar;23(3):416-422. doi: 10.1016/j.ajt.2022.11.001. Epub 2023 Jan 12. PMID: 36748802.