539 Phase 1 study of mRNA-2752, a lipid nanoparticle encapsulating mRNAs encoding human OX40L/IL-23/IL-36γ, for intratumoral (ITu) injection +/- durvalumab in advanced solid tumors and lymphoma

BackgroundmRNA-2752 is a novel mRNA-based therapeutic agent encoding OX40L T cell co-stimulator, IL-23 and IL-36γ pro-inflammatory cytokines. Preclinical data demonstrate synergy in combination with PD-L1 blockade.MethodsThis study evaluated the safety and efficacy of ITu mRNA-2752 administered Q2W up to 7 doses as monotherapy (Arm A) or in combination with the PD-L1 inhibitor durvalumab (Arm B) in patients (pts) with palpable tumors or tumors accessible with image guidance. Biomarker analyses included IHC of immune markers, whole transcriptome assessments, and protein evaluations of IL-23, IL-36γ and pro-inflammatory cytokines in pre- and post-treatment tumor biopsies and plasma. A PK/PD model was built to capture the IL-23 serum concentrations at the Q2W regimen to predict the exposure at the QW regimen to support an exploratory cohort.ResultsAs of 08April 2021, 49 pts were treated: Arm A (n=19) and Arm B (n=30) at doses ranging from 0.25 to 8mg Q2W. Treatment emergent adverse events (TEAEs) occurring in ≥ 10% of pts included Gr 1/2 injection site erythema/pain/swelling, fever, chills, fatigue, AST/ALT increase, lumbar myalgia, and maculopapular rash. One DLT of cytokine release syndrome was seen at the 8mg dose in Arm B. A squamous-cell bladder cancer and DLBCL have achieved confirmed PRs on Arm B, ongoing for 23 and 16 cycles, respectively. Biomarker analyses show increased IL-23 and IL-36γ protein expression, and their respective downstream cytokines IL-22 and IL-6, in tumor and plasma 6–24h after dosing; most cytokines assessed were elevated after treatment. Increased IFNγ and TNFα in tumor and plasma, sustained increases in interferon response genes including PD-L1 and markers of T cell infiltration, and activation in the TME (particularly in pts achieving a PR) indicate pro-inflammatory treatment effects with mRNA-2752 +/- durvalumab. PK/PD modeling showed the Cmax of IL-23 serum concentration of mRNA-2752 at 8mg approached a plateau, and simulations showed increasing the dosing frequency from Q2W to QW vs. dose increase may have a greater effect on increasing drug exposure.ConclusionsITu mRNA-2752 is safe and tolerable when combined with durvalumab. The recommended dose for expansion is 8mg mRNA-2752. Analyses of tumor and plasma biomarkers suggest a sustained treatment effect that includes elevated IFNγ, TNFα, and PD-L1 levels, providing rationale for combination therapy. Enrollment is ongoing in expansion cohorts of TNBC, urothelial cancer, lymphoma, immune-checkpoint refractory melanoma and NSCLC. PK/PD modeling supports QW dosing which is being explored in cutaneous melanoma in the neoadjuvant setting.Trial RegistrationNCT03739931ReferencesHewitt SL, Bai A, Bailey D et al. Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs. Sci Transl Med. 2019;11(477):1–15.Ethics ApprovalThe study was approved by the respective participating Institution’s Ethics Board and conducted in accordance with the International Council for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice and all applicable government regulations.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Small cell carcinoma of the bladder: A population-based analysis of long-term outcomes after radical cystectomy and bladder conservation with chemoradiotherapy

Introduction: We aimed to describe the oncological outcomes after radical cystectomy and chemo-radiation for localized small cell bladder cancer (SCBC). Methods: This population-based analysis of localized SCBC from 1985–2018 in British Columbia included an analysis (analysis 1) of cancer-specific survival (CSS) and overall survival (OS) of patients treated with curative-intent radical cystectomy (RC) and radiation (RT), and an analysis (analysis 2) of CSS and OS in patients treated with RC and chemoRT consistent with the SCBC Canadian consensus guideline. Results: Seventy-seven patients who were treated with curative intent were identified: 33 patients had RC and 44 had RT. For analysis 1, five-year OS was 29% and 39% for RC and RT, respectively (p=0.51), and five-year CSS was 35% and 52% for RC and RT, respectively (p=0.29). On multivariable analysis, higher Charlson comorbidity index (CCI) and the lack of neoadjuvant chemotherapy (NACHT) were associated with worse OS, while higher CCI and Eastern Cooperative Oncology Group (ECOG) were associated with worse CSS. For analysis 2, five-year OS was 56% and 58% for the RC and chemoRT groups, respectively (p=0.90), and five-year CSS was 56% for RC and 71% for chemoRT (p=0.71). Four of 42 (9.5%) chemoRT patients had RC at relapse. Conclusions: SCBC is a rare entity with a poor prognosis. RC and chemoRT offer similar CSS and OS for localized SCBC, even when focusing the analysis on patients treated according to the modern consensus guidelines. NACHT should be considered for eligible patients. Both chemoRT and RC treatment options should be discussed with patients with SCBC.

Bladder squamous cell carcinoma in a pregnant woman: case report and review of the literature

Background Bladder tumors in pregnancy are extremely rare. No more than 50 cases have been published to date, including all histologic variants, and only three cases of bladder squamous cell carcinoma have been described. Case presentation We present a clinical case of a 31-year-old woman with bladder squamous cell carcinoma in the second trimester of pregnancy. After a C-section at 30 weeks, we performed radical cystectomy with extended bilateral lymphadenectomy, hysterectomy and right oophorectomy. The Studer neobladder technique was performed for urinary tract reconstruction. Definitive pathology showed invasive bladder squamous cell carcinoma, Grade 2, with microscopic infiltration of the perivesical fat, negative margins, and 3/28 lymph nodes with carcinoma (pT3aN2M0). The patient underwent 18 months of surveillance after radical cystectomy, without recurrence by PET-CT. Conclusions Bladder cancer in pregnant women is extremely rare but must be considered in those with recurrent gross hematuria and/or recurrent urinary tract infection. To our knowledge, this case involves the longest recurrence-free survival of a pregnant woman with squamous cell bladder cancer published thus far.

Major Durable Response of Pembrolizumab in Chemotherapy Refractory Small Cell Bladder Cancer: A Case Report

Small cell carcinoma of the urinary bladder is a rare subtype (incidence of 1–9/1,000,000), characterized by an aggressive behavior with early metastasis and poor prognosis. Chemotherapy, radiation, and surgery are the usual treatment options, but to date, no accepted standard treatment exists. Since small cell bladder cancer shares similar clinicopathological features with small cell lung cancer, the same type of chemotherapy has been used. Recently, immune checkpoint inhibitors have shown effect in small cell lung cancer, but data regarding small cell bladder cancer is insufficient. Here we present a case where a 73-year-old male with chemorefractory metastatic small cell bladder cancer received a successful treatment with immune checkpoint inhibitor pembrolizumab resulting in a major durable response and no side effects. To our knowledge, this is the second case report on successful treatment of the rare subtype of small cell bladder cancer with an immune checkpoint inhibitor, supporting the use of pembrolizumab as a therapeutic option for small cell bladder cancer. Serum neuron-specific enolase was a useful biomarker both for chemo- and immunotherapy response.