Immune checkpoint inhibitors have changed the treatment landscape for various malignancies; however, their benefit is limited to a subset of patients. The immune machinery includes both mediators of suppression/immune evasion, such as PD-1, PD-L1, CTLA-4, and LAG-3, all of which can be inhibited by specific antibodies, and immune-stimulatory molecules, such as T-cell co-stimulatory receptors that belong to the tumor necrosis factor receptor superfamily (TNFRSF), including OX40 receptor (CD134; TNFRSF4), 4-1BB (CD137; TNFRSF9), and glucocorticoid-induced TNFR-related (GITR) protein (CD357; TNFRSF18). In particular, OX40 and its binding ligand OX40L (CD134L; TNFSF4; CD252) are critical for immunoregulation. When OX40 on activated T cells binds OX40L on antigen-presenting cells, T-cell activation and immune stimulation are initiated via enhanced T-cell survival, proliferation and cytotoxicity, memory T-cell formation, and abrogation of regulatory T cell (Treg) immunosuppressive functions. OX40 agonists are in clinical trials both as monotherapy and in combination with other immunotherapy agents, in particular specific checkpoint inhibitors, for cancer treatment. To date, however, only a minority of patients respond. Transcriptomic profiling reveals that OX40 and OX40L expression vary between and within tumor types, and that only ~ 17% of cancer patients have high OX40 and low OX40L, one of the expression patterns that might be theoretically amenable to OX40 agonist enhancement. Taken together, the data suggest that the OX40/OX40L machinery is a critical part of the immune stimulatory system and that understanding endogenous expression patterns of these molecules and co-existing checkpoints merits further investigation in the context of a precision immunotherapy strategy for cancer therapy.

For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT. Therefore, we assessed stem cell mobilization in patients following frontline induction therapy in the MASTER and GRIFFIN phase 2 clinical studies by examining stem cell mobilization yields, apheresis attempts, and engraftment outcomes for patients from each study. Adult transplantation-eligible patients with NDMM received induction therapy consisting of daratumumab plus carfilzomib/lenalidomide/dexamethasone (D-KRd) for four 28-day cycles in the single-arm MASTER trial or lenalidomide/bortezomib/dexamethasone (RVd) with or without daratumumab (D) for four 21-day cycles in the randomized GRIFFIN trial, followed by stem cell mobilization and ASCT in both studies. Institutional practice differed regarding plerixafor use for stem cell mobilization; the strategies were upfront (ie, planned plerixafor use) or rescue (ie, plerixafor use only after mobilization parameters indicated failure with granulocyte colony-stimulating factor [G-CSF] alone). Descriptive analyses were used to summarize patient characteristics, stem cell mobilization yields, and engraftment outcomes. In MASTER, 116 D-KRd recipients underwent stem cell mobilization and collection at a median of 24 days after completing induction therapy. In GRIFFIN, 175 patients (D-RVd, n = 95; RVd, n = 80) underwent mobilization at a median of 27 days after completing D-RVd induction therapy and 24 days after completing RVd induction therapy. Among those who underwent mobilization and collection, 7% (8 of 116) of D-KRd recipients, 2% (2 of 95) of D-RVd recipients, and 6% (5 of 80) of RVd recipients did not meet the center-specific minimally required CD34⁺ cell yield in the first mobilization attempt; however, nearly all collected sufficient stem cells for ASCT on remobilization. Among patients who underwent mobilization, plerixafor use, either upfront or as a rescue strategy, was higher in patients receiving D-KRd (97%; 112 of 116) and D-RVd (72%; 68 of 95) compared with those receiving RVd (55%; 44 of 80). The median total CD34⁺ cell collection was 6.0 × 10⁶/kg (range, 2.2 to 13.9 × 10⁶/kg) after D-KRd induction, 8.3 × 10⁶/kg (range, 2.6 to 33.0 × 10⁶/kg) after D-RVd induction, and 9.4 × 10⁶/kg (range, 4.1 to 28.7 × 10⁶/kg) after RVd induction; the median days for collection were 2, 2, and 1, respectively. Among patients who underwent mobilization, 98% (114 of 116) of D-KRd patients, 99% (94 of 95) of D-RVd patients, and 98% (78 of 80) of RVd patients underwent ASCT using median CD34⁺ cell doses of 3.2 × 10⁶/kg, 4.2 × 10⁶/kg, and 4.8 × 10⁶/kg, respectively. The median time to neutrophil recovery was 12 days in all 3 treatment groups across the 2 trials. Because both trials used different criteria to define platelet recovery, data on platelet engraftment using the same criteria are not available. Four cycles of daratumumab- and lenalidomide-based quadruplet induction therapy had a minimal impact on stem cell mobilization and allowed predictable stem cell harvesting and engraftment in all patients who underwent ASCT. Upfront plerixafor strategy may be considered, but many patients were successfully collected with the use of G-CSF alone or rescue plerixafor.

Metaplastic breast cancer (MBC) is a rare neoplasm accounting for <1% of all breast cancer. We evaluated the clinical characteristics and survival outcomes of MBC. Patients diagnosed with pathologically proven MBC were reviewed from the institutional breast cancer database from 2000 to 2017. A total of 136 patients diagnosed with MBC were included in the study. The median age of the diagnosis was 60 years, and 60% of patients were stage II at diagnosis, and 22% were stage III. About two-thirds of the patients were triple-negative; 93% had nuclear grade III, and 25% had a lymphovascular invasion. Squamous differentiation (29%) was the most common histologic subtype, followed by the spindle subtype (21%). The most common distant metastases were lung (22%), followed by bone (13%). Moreover, 60% had a mastectomy, 19% had endocrine therapy, 58% had radiation, 51% received anthracycline-based chemotherapy, 26% had non-anthracycline chemotherapy, and 22% received no chemotherapy. In the entire cohort, the two-year overall survival (OS) and five-year OS were 79% and 69%, respectively, and the two-year progression-free survival (PFS) and five-year PFS were 72% and 61%, respectively. On multivariable analysis, the stage of MBC (stage III: hazard ratio (HR), 5.065 (95% confidence interval (CI), 1.02-25.27) (p=0.048)), poor functional status (Eastern Cooperative Oncology Group (ECOG) score, 2; HR, 24.736 (95% CI, 1.92-318.73) (p=0.014)), and distant metastasis to the brain (HR, 8.453 (95% CI, 1.88-38.04) (p=0.005)) and lung (HR, 42.102 (95% CI, 7.20-246.36) (p<0.001)) were significant predictors of decreased OS. MBC demonstrated early disease progression and poor overall survival. The stage of MBC, decreased performance status, and metastasis to the lung and brain were independent poor prognostic factors.