Despite advancements in current cancer treatments, surgical resection remains to date the gold standard in the treatment of oral squamous cell carcinoma (OSCC). Primary chemoradiation (CRT), can be considered as an alternative treatment in cases of locoregional advanced diseases or patients declining surgery. The aim was to assess the clinical and oncological outcome of patients with OSCC receiving CRT. In this retrospective cohort study, all patients receiving primary CRT between 01/2013-12/2023 were assessed. Endpoints of this study were the overall survival (OS), the rate of osteoradionecrosis of the jaw (ORNJ) and the recurrence-free survival (RFS). Overall, 125 patients were included. During follow-up, 42.4 % of patients developed local recurrence and 11.3 % cervical lymph node metastasis. The overall rate of distant metastasis was 24.8 %, which was significantly higher in patients with locoregional recurrence (39.6 % vs. 13.9 %, p < 0,01). The rate of ORNJ was 5.9 %. The 3-year OS and RFS were 30.2 % and 34.0 %, respectively. UICC-stage IVB and ECOG-score 2 were independently associated with worse OS. There was a trend towards the association of salvage surgery in case of locoregional recurrence with a 69 % reduction in the risk of death. In this study, primary CRT for OSCC was associated with poor outcome. These findings highlight on one hand the relevance of surgery in cases of resectable tumors and on the other hand the need for further improvements towards the patient population with irresectable tumors, where primary CRT is currently the only guideline-supported treatment option.

The emergence of CAR-T cell therapy has transformed the treatment of the previously refractory/relapsed multiple myeloma (MM). Yet, autologous CAR-T cells suffer from inconsistent manufacturing, long manufacturing timelines, and high cost, which can limit patient accessibility. To address these issues, we engineered a fully allogeneic anti-BCMA CAR-T cell candidate for MM from healthy donors (P-BCMA-ALLO1). Herein, we demonstrate that P-BCMA-ALLO1 maintains a T stem cell memory phenotype (T SCM) through genetic editing, which correlates with antitumor efficacy. Using Poseida's proprietary non-viral piggyBac® (PB) DNA Delivery System, in combination with the high-fidelity Cas-CLOVER™ (CC) Site-Specific Gene Editing System and a proprietary "booster molecule", we generated P-BCMA-ALLO1 from healthy donor T cells. We used CC to eliminate surface expression of TCR and MHC class I to make fully allogeneic CAR-T cells. In addition to the CAR molecule, PB enables the delivery of a selectable marker allowing the generation of a final cell product that is >95% CAR-positive. The inclusion of the "booster molecule" in the manufacturing process improves the expansion of gene-edited cells without compromising memory phenotype or function. This process can produce up to hundreds of patient doses from a single manufacturing run using one healthy donor, thereby significantly reducing manufacturing cost per dose. We characterized the phenotype and functionality of P-BCMA-ALLO1 using flow cytometry and Nanostring to assess their memory phenotype at both the protein and mRNA levels. Also analyzed was antitumor toxicity and proliferative capacity through multiple rounds of activation using in vitro co-culture assays and serial restimulation, respectively. The relationship of all characterizations with in vivo efficacy was then determined, as defined by control of tumor growth in an immunodeficient RPMI-8226 subcutaneous murine tumor model. We found that P-BCMA-ALLO1 is comprised of a high frequency of T SCM after editing (Fig. 1), and the maintenance of that memory phenotype correlates with antitumor efficacy. In vivo, these CAR-T cells are potent in controlling tumor growth, comparable to or better than autologous anti-BCMA CAR-T cells. Our analysis revealed that the expression of memory markers at the surface protein level (CD27, CD62L, CD127, CCR7) and mRNA level significantly correlate with in vivo tumor control. Conversely, suboptimal research products with worse in vivo outcomes express a more exhausted gene expression profile. We reveal from our analysis that the most effective P-BCMA-ALLO1 in vivo share similar characteristics: (1) these products were a result of efficient manufacturing, with >90% CAR+ and >99% TCR-; (2) they carry a memory phenotype, with 50-70% T scm and high proliferative capacity after multiple rounds of restimulation; (3) they are >90% viable; and (4) they show strong antitumor efficacy both in vitro and in vivo. We demonstrate that Tscm percentage in the final product correlates with antitumor activity. P-BCMA-ALLO1 is advancing rapidly towards the clinic (NCT04960579) to positively impact the outcomes of CAR-T therapy for MM patients. Figure 1: Memory composition of P-BCMA-ALLO1 research products. P-BCMA-ALLO1 consists mostly of stem cell memory (T scm) and central memory (T cm) T cells that are CD62L + as opposed to effector memory (T em) and effector (T eff) T cells. Figure 1 Figure 1. Disclosures: Tseng: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhang: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Cranert: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Richter: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Marquez: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Qiu: Poseida Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Cho: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tan: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tong: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Domingo: Poseida Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Weiss: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Argus: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sparks: Poseida Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Ostertag: Poseida: Current Employment, Current equity holder in publicly-traded company. Coronella: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company. Shedlock: Poseida Therapeutics: Current Employment, Current equity holder in publicly-traded company.

Oral squamous cell carcinoma (OSCC) with bone invasion are staged as pT4a, potentially upstaging smaller tumors. This study aimed to evaluate the oncological benefit of postoperative radiotherapy (PORT) in pT4aN0 OSCC with respect to tumor size and without other risk factors. This retrospective matched cohort study included pT4aN0 OSCC patients with bone invasion treated surgically (R0) between 2010 and 2022. Each case was 1:1 matched to a pT1-3 N0 OSCC patient based on tumor size, but without bone invasion. The primary endpoint was overall survival (OS), secondary endpoints included the recurrence-free survival and outcome predictors. A total of 156 patients were analyzed (78 per group). There were no statistically significant differences in 3-year OS between both groups in general (78.2%, 95%CI: 68.6-87.8 vs. 80.0%, 95%CI: 68.4-91.6). After stratification for pT2 criteria, there was also no significant difference between both groups if PORT was omitted (63.9%, 95%CI: 44.2-92.4 vs. 70.5%, 95%CI: 55.0-90.0). Multivariate analysis identified age and poor differentiation (grade III) as significant predictors of worse OS, while PORT showed no independent survival benefit. In small OSCC staged pT4a due to bone invasion and lacking other risk factors, PORT demonstrated no statistically significant improvement in OS when matched for tumor size. Further prospective trials and larger cohorts are warranted to confirm these findings.

Microvascular free flap reconstruction is a standard technique in head and neck surgery with high success rates. Nevertheless, complications like early flap loss, locoregional recurrence of head and neck cancer and osteoradionecrosis may require further flap procedures. This study aims to assess outcomes and challenges associated with subsequent free flap procedures. In this retrospective cohort study, all patients who received subsequent free flaps between January 2013 and December 2022 were assessed and examined by explorative descriptive analysis. Furthermore, one exemplary case is presented. Overall, 69 patients with 150 free flaps were included, with up to 4 subsequently performed flaps. Reasons for subsequent flaps included early failure, local cancer recurrence, osteoradionecrosis and wound healing disorders. After early failures, subsequent flaps were successful in 97 % of this cohort. The more flaps were performed, the more likely the contralateral neck was used for vascular anastomosis and the more likely vein grafts were used. Subsequent free flap procedures are safe and viable options in head and neck reconstruction, even in cases of previous flap failure. Even if previous surgeries, already harvested flaps and radiation therapy might complicate the choice of reconstruction, this should not be a deterrent to achieve consistent rehabilitation of the patient.

Objective: Despite numerous studies addressing the impact of p16^INK4a in oral squamous cell carcinoma (OSCC), consistent data regarding survival and tumor proliferation behavior are lacking. Although some authors investigate both p16^INK4a and Mib/Ki-67 in their cohorts, direct correlations are consistently missing. The aim of this study was to investigate the combined influence of p16^INK4a and Mib/Ki-67 status on prognosis in OSCC.Materials and methods: Clinical data of all patients diagnosed with OSCC and treated curatively between 2005 and 2011 were collected retrospectively. Tissue microarrays of formalin-fixed paraffin-embedded specimens were stained for p16^INK4a and Mib/Ki-67 using the CINtec Histology V-Kit or MIB-1 antibody and correlated with the clinical outcome.Results: A total of 316 patients, with a mean age of 61.7 years were included. Tumor tissues that were tested p16^INK4a positive with low Mib/Ki-67 expression demonstrated a remarkable 5-year survival rate of 83% with an improved RFS compared to all other subgroups (p=0.034; p=0.017; p=0.026) and an improved OS compared to those with high Mib/Ki-67 expression (p=0.026; p=0.020). Cox regression identified the combined p16^INK4a and Mib/Ki-67 status as a risk factor on OS (HR 6.25; CI1.26-31.0; p=0.025) and RFS (HR 5.88; CI1.19-29.20; p=0.030).Conclusion: These results underscore the importance of a combined assessment of p16^INK4a and Mib/Ki-67 in evaluating the prognosis of OSCC, leading to the identification of distinct subgroups that may serve as risk factors for treatment stratification.

Objective: The T classification of oral squamous cell carcinoma (OSCC) is linear according to the tumor size, excluding T4a by its criteria of invasion into adjacent structures, such as cortical bone. This may lead to the upstaging of otherwise small tumors. The objective was to analyze patients with OSCC and negative nodal staging to assess the impact of T-staging with tumor size on the incidence of occult cervical lymph node metastasis (CLNM) and regional neck failure. Methods: This retrospective cohort study included patients with OSCC and clinically negative necks (cN0), treated surgically between 2010 and 2024. All T4a OSCC classified due to bone invasion were additionally reclassified into T1–T3 based on size and depth of invasion according to the current staging manual. The primary endpoint of this study was the association between OSCC stratified by T-stage and tumor size as well as the presence of occult CLNM. Results: A total of 642 patients were included, with an overall occult CLNM rate of 20.2%. Bone invasion in T1-sized tumors was significantly associated with occult CLNM (OR 6.38, 95% CI: 1.48–27.42), whereas no such association was observed in T2 or T3 tumors (OR 0.80, 95% CI: 0.37–1.73; and OR 0.77, 95% CI: 0.37–1.62, respectively). Additionally, in T1–T2 tumors, bone invasion did not correlate with worse survival outcomes. Conclusions: Bone invasion was not significantly associated with occult CLNM in T2-3 sized OSCC, suggesting that the prognostic relevance is size-dependent. These findings question the uniform upstaging to T4a and support a more differentiated approach, potentially enabling neck management de-escalation in selected early-stage cases.