Elimination of Human Papillomavirus 16-Positive Tumors by a Mucosal rAd5 Therapeutic Vaccination in a Pre-Clinical Murine Study.

Therapeutic vaccination can harness the body's cellular immune system to target and destroy cancerous cells. Several treatment options are available to eliminate pre-cancerous and cancerous lesions caused by human papillomaviruses (HPV), but may not result in a long-term cure. Therapeutic vaccination may offer an effective, durable, and minimally intrusive alternative. We developed mucosally delivered, recombinant, non-replicating human adenovirus type 5 (rAd5)-vectored vaccines that encode HPV16's oncogenic proteins E6 and E7 alongside a molecular dsRNA adjuvant. The induction of antigen-specific T cells and the therapeutic efficacy of rAd5 were evaluated in a mouse model of HPV tumorigenesis where E6E7-transformed cells, TC-1, were implanted subcutaneously in C57BL/6 mice. After tumor growth, mice were treated intranasally with rAd5 vaccines expressing the wildtype form of E6E7 (rAd5-16/E6E7Wt) in combination with an anti-PD-1 antibody or isotype control. Animals treated with rAd5-16/E6E7Wt with and without anti-PD-1 had significant reductions in tumor volume and increased survival compared to controls. Further, animals treated with rAd5-16/E6E7Wt had increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and produced a cytotoxic tumor microenvironment. In a second study, the immunogenicity of a non-transformative form of E6E7 (rAd5-16/E6E7Mu) and a vaccine encoding predicted T cell epitopes of E6E7 (rAd5-16/E6E7epi) were evaluated. These vaccines elicited significant reductions in TC-1 tumor volume and increased survival of animals. Antigen-specific CD8+ T effector memory cells were observed in the animals treated with E6E7-encoding rAd5, but not in the rAd5-empty group. The work described here demonstrates that this mucosal vaccination can be used therapeutically to elicit specific cellular immunity and further identifies a clinical candidate with great potential for the treatment and prevention of human cervical cancer.

CREST-UK: Real-world effectiveness, safety and outpatient delivery of CPX-351 for first-line treatment of newly diagnosed therapy-related AML and AML with myelodysplasia-related changes in the UK.

Favourable outcomes with CPX-351 versus conventional 7 + 3 were demonstrated in the pivotal phase III trial in adults aged 60-75 years with newly diagnosed, highrisk/secondary acute myeloid leukaemia (AML). As a complement to the clinical trial and to address important data gaps, the CPX-351 Real-World Effectiveness and SafeTy (CREST-UK; NCT05169307) study evaluated the use of CPX-351 in routine clinical practice in the UK, in 147 patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Best response of complete remission or complete remission with incomplete platelet or neutrophil recovery was achieved by 53% of evaluable patients. Kaplan-Meier median overall survival (OS) was 12.8 months (95% confidence interval 9.2-15.3). Fifty (34%) patients proceeded to haematopoietic cell transplantation (HCT); median OS landmarked from the HCT date was not reached. There were no new safety concerns with CPX-351 identified in CREST-UK. Patients treated with CPX-351 in the outpatient setting spent an average of 24.4, 16.7, 28.2, and 27.7 fewer days on the ward compared with inpatients during first induction, second induction, first consolidation, and second consolidation, respectively. The results from CREST-UK provide valuable insights into the effectiveness, safety, and outpatient delivery of CPX-351 in routine clinical practice in the UK.

FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML.

Patients with FLT3-mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure.  This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated.  We identified 56 patients treated with FLT3i at molecular failure.  The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib (n = 38), quizartinib (n = 7) or sorafenib (n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69-93) and molecular event-free survival 56% (95%CI 44-72). High-sensitivity next-generation sequencing for FLT3-ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.

A retrospective quantitative implementation evaluation of Safer Opioid Prescribing, a Canadian continuing education program.

BACKGROUND: Continuing health professions education (CHPE) is an important policy intervention for the opioid epidemic. Besides effectiveness or impact, health policy implementation should be studied to understand how an intervention was delivered within complex environments. Implementation outcomes can be used to help interpret CHPE effects and impacts, help answer questions of "how" and "why" programs work, and inform transferability. We evaluated Safer Opioid Prescribing (SOP), a national CHPE program, using implementation outcomes of reach, dose, fidelity, and participant responsiveness. METHODS: We conducted a retrospective quantitative implementation evaluation of the 2014-2017 cohorts of SOP. To measure reach and dose, we examined participation and completion data. We used Ontario physician demographic data, including regulatory status with respect to controlled substances, to examine relevant trends. To measure fidelity and participant responsiveness, we analyzed participant-provided evaluations of bias, active learning, and relevance to practice. We used descriptive statistics and measures of association for both continuous and categorical variables. We used logistic regression to determine predictors of workshop participation and analysis of covariance to examine variation in satisfaction across different-sized sessions. RESULTS: Reach: In total, there were 472 unique participants, 84.0% of whom were family physicians. Among Ontario physician participants, 90.0% were family physicians with characteristics representative of province-wide demographics. Dose: Webinar completion rate was 86.2% with no differences in completion based on rurality, gender, or controlled substance prescribing status with medical regulatory authorities. Fidelity and participant responsiveness: Nearly all participants rated the three webinars and workshop as balanced, and each element of SOP was also rated as highly relevant to clinical practice. CONCLUSIONS: This evaluation demonstrates that Safer Opioid Prescribing was implemented as intended. Over a short period and without any external funding, the program reached more than 1% of the Ontario physician workforce. This suggests that the program may be a good model for using virtual CHPE to reach a critical mass of prescribers. This study represents a methodological advance of adapting evaluation methods from health policy and complex interventions for continuing health professions education. Future studies will assess effectiveness and impact on opioid prescribing and utilization within evaluation models of complex interventions.