Rational design of chimeric antigen receptor T (CAR-T) cells based on the recognition of antigenic epitopes capable of evoking the most potent CAR activation is an important objective in optimizing immune therapy. In solid tumors, the B7-H3 transmembrane protein is an emerging target that harbours two distinct epitope motifs, IgC and IgV, in its ectodomain. Here, we generate dromedary camel nanobodies targeting B7-H3 and demonstrate that CAR-T cells, based on the nanobodies recognizing the IgC but not IgV domain, had potent antitumour activity against large tumors in female mice. These CAR-T cells are characterized by highly activated T cell signaling and significant tumor infiltration. Single-cell transcriptome RNA sequencing coupled with functional T-cell proteomics analysis uncovers the top-upregulated genes that might be critical for the persistence of polyfunctional CAR-T cells in mice. Our results highlight the importance of the specific target antigen epitope in governing optimal CAR-T activity and provide a nanobody-based B7-H3 CAR-T product for use in solid tumor therapy.

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematological malignancy in the world. The MM tumor microenvironment (TME) within the BM niche consists of a wide range of elements which play important roles in supporting MM disease progression, survival, proliferation, angiogenesis, as well as drug resistance. Together, the TME fosters an immunosuppressive environment in which immune recognition and response are repressed. Macrophages are a central player in the immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing direct and indirect immune responses in cancer. Tumor-associated macrophages (TAMs) are a major population of cells in the tumor site. Rather than contributing to the immune response against tumor cells, TAMs in many cancers are found to exhibit protumor properties including supporting chemoresistance, tumor proliferation and survival, angiogenesis, immunosuppression, and metastasis. Targeting TAM represents a novel strategy for cancer immunotherapy, which has potential to indirectly stimulate cytotoxic T cell activation and recruitment, and synergize with checkpoint inhibitors and chemotherapies. In this review, we will provide an updated and comprehensive overview into the current knowledge on the roles of TAMs in MM, as well as the therapeutic targets that are being explored as macrophage-targeted immunotherapy, which may hold key to future therapeutics against MM.

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM.

E18534 Background: Mammography screening significantly reduces breast-cancer related mortality; however, many women fail to undergo screening as recommended by national guidelines. No-shows are responsible for a significant proportion of delayed or missed cancer screening exams. Further, no-shows disproportionately affect underserved and minority populations. We previously identified a high no-show rate for screening mammograms among patients seeking care our institution. African American (AA) women were almost three times more likely to no-show than non-Hispanic white women. The racial disparity in no-shows persisted after adjustment for socioeconomic factors. The objective of this survey study was to identify reasons for missed mammogram screening appointments among AA women. Methods: We conducted a survey (via mail or telephone) of AA women who missed their screening mammogram appointment in summer 2021. Using a structured survey instrument, we collected information on patient-specific and health service barriers. Patient-specific barriers included procedure-related concerns (e.g., concern about discomfort), cognitive-emotional factors (e.g., fear of finding cancer), and changes in health status. Health service barriers included logistical factors (e.g., transportation), cost (e.g., lack of insurance) and scheduling problems (e.g., forgot about appointment or scheduled at an inconvenient time). Here we describe the most common reasons for missed appointments and compared women who reported patient-specific versus health service barriers. Results: 255 women who no-showed for their appointment were contacted and 91 participated in the study survey (35.6% response rate). Most respondents (90%) attributed their no-show to at least one of the listed barriers. Nineteen (7.5%) attributed their no-show to COVID-19, but only 1 person reported this as their only barrier. Scheduling issues were the most commonly reported barriers (57.8%), followed by transportation (38.9%). Three-quarters of respondents reported health service barriers, while only 40.7% reported patient-related barriers. The most common patient-related barriers were cognitive-emotional (25%), changes in health status (20.9%) and procedure-related concerns (15.6%). The majority of respondents (82.6%) were interested in rescheduling their mammogram. Conclusions: Most appointment no-shows among surveyed AA women resulted from potentially preventable scheduling and transportation issues. Relatively few respondents reported cognitive-emotional or procedure-related concerns. Further, the majority of respondents were interested in rescheduling their mammogram; which suggests that these women remain motivated to undergo breast cancer screening. Programs which address preventable health-service related issues may help these women keep their appointments.