Abstract Purpose: First-in-human Phase I study for advanced MUC1* positive breast cancer with autologous T cells engineered to express either a chimeric antigen receptor, huMNC2-CAR44 or huMNC2-CAR22, which specifically bind to a cleaved form of MUC1 (MUC1*); evaluate the safety and preliminary anti-tumor activity. Methods: MUC1* (muk 1 star) is the growth factor receptor form of MUC1, created by cleavage and release of the N-terminal portion of MUC1. The targeting antibody, huMNC2, only recognizes the conformational epitope created when MUC1 is cleaved by specific tumor-associated enzymes that are correlated with poor prognosis. huMNC2 does not bind to full-length MUC1, which is expressed on all normal epithelial cells. huMNC2-scFv was incorporated into huMNC2-CAR44, comprising a CD8 hinge and transmembrane region, 4-1BB costimulatory domain and wild-type CD3z. huMNC2-scFv was also incorporated into huMNC2-CAR22 wherein the hinge, transmembrane and co-stimulatory portions were derived from CD28 and CD3z bears the 1XX mutations to increase in vivo persistence. Inclusion criteria require that the patient’s tumor is at least 30% MUC1* positive and that patient has progressed through 2 or 3 prior therapies, while in the metastatic setting. Patients receive standard Cy/Flu lymphodepletion approximately 3-days before CAR T treatment, administered at 1 of 4 dose levels ranging from 3.3X10^5 up to 1.0X10^7 CAR+ T cells. Results: To date, 8 patients have been treated with huMNC2-CAR44. No patients experienced neuro toxicities. No off-target toxicities were observed. 3 patients experienced CRS Grade 1-3. In 6 of the 8 patients, side effects were non-existent or minimal. However, one patient experienced a Grade 5 SAE that was deemed to be possibly related to the treatment. Best responses include Partial Responses and Stable Disease at a low CAR-T dose. Greatest efficacy was observed for patients whose biopsy showed H Scores >120. Patients are currently being enrolled for treatment with huMNC2-CAR22, where the 1XX mutations are expected to increase in vivo persistence, durability of response and reduced incidence of CRS. Conclusions: These data support a conclusion that the MUC1* antibody, huMNC2, is safe and could have high therapeutic value as a CAR T treatment for solid tumors with moderate to high antigen density. As the huMNC2-CAR22 (1XX) trial proceeds, we will assess if patient responses mirror our animal results that show that the 1XX mutations confer increased persistence, reduced exhaustion and the ability to kill tumors with low antigen density. Citation Format: Cynthia Carol Bamdad, Joanne E. Mortimer, Yuan Yuan, Jennifer M. Specht, Andrew K. Stewart, Benoit J. Smagghe, Stephen C. Lin, Mark G. Carter, Tim W. Synold, Mark D. Fleming, Stanley R. Hamilton, Vishwas Parekh, Danica M. Walkley, Qing Liu-Michael, Kevin R. Yi, Jac-Leen S. Nash, Michael J. Nash, Stephen J. Forman. Phase I first-in-human MUC1* targeted autologous CAR T cells for the treatment of metastatic breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT096.

Background: Tumor reactive or activated-by-cytokine killers (TRACK) are PD-L1+ highly cytolytic natural killer (NK) cells derived from umbilical cord blood NK cells that are engineered to express soluble IL15 (sIL15). sIL15_TRACK NK cells have shown promise in preclinical studies against human non-small cell lung cancer (NSCLC) (PMID: 38572955). Here we demonstrate sIL15_TRACK NK cells traffic to the patients' solid tumor site, survive at the tumor site and retain cytotoxic function at the tumor site. Three of six patients, all with progressive disease at the time of study enrollment, achieved stable disease following the infusions of sIL15_TRACK NK cells. Methods: This first-in-human phase 1 trial (NCT05334329) evaluated the initial safety, tolerability, and preliminary efficacy of unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cells in six patients with advanced, previously treated NSCLC that were relapsed from or refractory to chemotherapy, refractory to immune checkpoint inhibition, and progressing at the time of enrollment. Patients received a standard lymphodepletion regimen (LDR) followed by 4 or 8 weekly infusions of sIL15_TRACK NK cells at one of two dose levels. NK cell persistence and cytotoxic activity were monitored using droplet digital PCR (ddPCR), flow cytometry, and immunofluorescent staining of a tumor biopsy. Results: The sIL15_TRACK NK cell therapy was delivered in the outpatient setting, was well-tolerated without severe adverse events related to the therapy. Common grade 1-2 toxicities included fatigue, nausea, and diarrhea, while grade 3-4 hematologic toxicities were likely related to the standard LDR. Pharmacokinetic studies demonstrated that sIL15_TRACK NK cells were measurable in blood hours after infusion and peak measurements increased weekly, suggesting an absence of host rejection even during the second cycle where cyclophosphamide was administered without fludarabine for the LDR. sIL15_TRACK NK cells were observed in a lung tumor biopsy 7 days following the final infusion, confirming their sustainment and tumor-homing ability. The engineered sIL15_TRACK NK cells express several cell activating receptors (e.g., NKG2D, DNAM-1, and NKp30) that bind to cognate ligands that we show to be expressed on a NSCLC patient biopsy (e.g., MICA/B, CD112, and BAG6, respectively), and retain their cytolytic function following isolation from the lung tumor tissue. At two low doses of cells tested (1.5 × 106 and 4.0 × 106 transduced cells/kg), three out of six patients (50%) achieved disease stabilization as best response on repeat imaging, while the remaining three showed progressive disease. Conclusion: Unmatched, allogeneic, off-the-shelf sIL15_TRACK NK cell therapy demonstrated a favorable safety profile and showed preliminary efficacy in stabilizing disease in a subset of patients with advanced and progressive NSCLC. The ability of engineered sIL15_TRACK NK cells to express activating receptors, home to tumor sites that express their cognate ligands, and retain cytolytic activity after infusion underscores their potential as a novel immunotherapeutic approach in solid tumors. Additional dose escalation cohorts and co-administration with atezolizumab are planned for a second stage of this trial.

An evaluation of patient satisfaction with pain management is one component of a total quality assurance program on pain management recommended by the American Pain Society. This study utilized the patient satisfaction survey recommended by the Quality Assurance Committee of the American Pain Society and was conducted in an acute care, municipal hospital. Seventy-two medical-surgical patients were interviewed about their pain management. Data from the survey suggest that while patients experienced moderate-to-severe pain and had to wait relatively long periods of time for pain medications, in most cases they were satisfied with their overall pain management. Recommendations for conducting patient satisfaction surveys of pain management in acute care settings are reviewed, and methods for interpreting data from these types of surveys are discussed.