Complete Response Patients Research Articles

Correlation between trophoblast cell-surface antigen-2 (Trop-2) expression and pathological complete response in patients with HER2-positive early breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab.

The prognostic and predictive role of trophoblast cell-surface antigen-2 (Trop-2) overexpression in human epidermal growth factor receptor 2-positive (HER2-positive) breast cancer is currently unknown. We retrospectively analyzed Trop-2 expression and its correlation with clinicopathologic features and pathological complete response (pCR) in HER2-positive early breast cancer (EBC) patients treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab in the PHERGain study. Trop-2 expression at baseline was determined in formalin-fixed, paraffin-embedded primary tumor biopsies by immunohistochemistry and was first classified into expressing (Trop-2-positive) or not-expressing (Trop-2-negative) tumors. Then, it was classified by histochemical score (H-score) according to its intensity into low (0-9), intermediate (10-49), and high (≥ 50). The association between clinicopathologic features, pCR, and Trop-2 expression was performed with Fisher's exact test. Forty-one patients with tissue evaluable for Trop-2 expression were included, with 28 (68.3%) Trop-2-positive tumors. Overall, 17 (41.46%), 14 (34.15%), and 10 (24.40%) tumors were classified as low, intermediate, and high, respectively. Trop-2 expression was significantly associated with decreased pCR rates (50.0% vs. 92.3%; odds ratio [OR] 0.05; 95% CI, 0.002-0.360]; p adjusted = 0.01) but was not correlated with any clinicopathologic features (p ≥ 0.05). Tumors with the highest Trop-2H-score were less likely to obtain a pCR (OR 0.03; 95% CI, 0.001-0.290, p adjusted < 0.01). This association was confirmed in univariate and multivariate regression analyses. These findings suggest a potential role of Trop-2 expression as a biomarker of resistance to neoadjuvant chemotherapy plus dual HER2 blockade and may become a strategic target for future combinations in HER2-positive EBC patients.

Long noncoding RNA XIST: a novel independent prognostic biomarker for patients with ABC-DLBCL receiving R-CHOP treatment.

Approximately one-third of activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cases were unresponsive to standard first-line therapy; thus, identifying biomarkers to evaluate therapeutic efficacy and assessing the emergence of drug resistance is crucial. Through early-stage screening, long noncoding RNA (lncRNA) X-inactive specific transcript (XIST) was found to be correlated with the R-CHOP treatment response. This study aimed to clarify the characteristics of XIST in ABC-DLBCL. The expression level of XIST in 161 patients with ABC-DLBCL receiving R-CHOP therapy was examined via RNA in situ hybridization, and the association between XIST expression and clinicopathological features, treatment response and prognosis was analyzed in the study cohort and validated in the Gene Expression Omnibus cohort. Cell biological experiments and bioinformatics analyses were conducted to reveal aberrant signaling. The proportion of complete response in patients with high XIST expression was lower than that in patients with low XIST expression (53.8% versus 77.1%) (P = 0.002). High XIST expression was remarkably associated with the characteristics of tumor progression and was an independent prognostic element for overall survival (P = 0.039) and progression-free survival (P = 0.027) in ABC-DLBCL. XIST was proven to be involved in m6A-related methylation and ATF6-associated autophagy. XIST knockdown repressed ABC-DLBCL cellular proliferation by regulating Raf/MEK/ERK signaling. High XIST expression was associated with ABC-DLBCL tumorigenesis and development and contributed to R-CHOP treatment resistance. XIST may be a promising signal to predict ABC-DLBCL prognosis.

Pathologic complete response in patients with esophageal cancer receiving neoadjuvant chemotherapy or chemoradiation: A systematic review and meta-analysis.

Neoadjuvant chemoradiation and chemotherapy are recommended for the treatment of nonmetastatic esophageal cancer. The benefit of neoadjuvant treatment is mostly limited to patients who exhibit pathologic complete response (pCR). Existing estimates of pCR rates among patients receiving neoadjuvant therapy have not been synthesized and lack precision. We conducted an independently funded systematic review and meta-analysis (PROSPERO CRD42023397402) of pCR rates among patients diagnosed with esophageal cancer treated with neoadjuvant chemo(radiation). Studies were identified from Medline, EMBASE, and CENTRAL database searches. Eligible studies included trials published from 1992 to 2022 that focused on nonmetastatic esophageal cancer, including the gastroesophageal junction. Histology-specific pooled pCR prevalence was determined using the Freeman-Tukey transformation and a random effects model. After eligibility assessment, 84 studies with 6451 patients were included. The pooled prevalence of pCR after neoadjuvant chemotherapy in squamous cell carcinomas was 9% (95% CI: 6%-14%), ranging from 0% to 32%. The pooled prevalence of pCR after neoadjuvant chemoradiation in squamous cell carcinomas was 32% (95% CI: 26%-39%), ranging from 8% to 66%. For adenocarcinoma, the pooled prevalence of pCR was 6% (95% CI: 1%-12%) after neoadjuvant chemotherapy, and 22% (18%-26%) after neoadjuvant chemoradiation. Under one-third of patients with esophageal cancer who receive neoadjuvant chemo(radiation) experience pCR. Patients diagnosed with squamous cell carcinomas had higher rates of pCR than those with adenocarcinomas. As pCR represents an increasingly utilized endpoint in neoadjuvant trials, these estimates of pooled pCR rates may serve as an important benchmark for future trial design.

Higher rate of pathologic complete response in patients with early-onset locally advanced rectal cancer

Higher rate of pathologic complete response in patients with early-onset locally advanced rectal cancer

Oncolytic virus CF33-hNIS monotherapy for the treatment of gastrointestinal (GI) malignancies.

749 Background: CF33-hNIS is a novel chimeric DNA vaccinia virus engineered with the human sodium-iodide symporter (hNIS) gene. CF33-hNIS selectively replicates in tumor cells leading to cell lysis and the release of tumor- and virus-associated antigens stimulating antitumor immunity. Here, we report results of patients with GI malignancies enrolled on a first-in-human phase 1 ascending, multiple dose, safety and tolerability study of CF33-hNIS, administered intratumorally (IT) or intravenously (IV) in adult patients with metastatic or advanced solid tumors (MAST). Methods: The MAST study is evaluating the safety of CF33-hNIS administered IT or IV, alone or in combination with pembrolizumab in patients with advanced or metastatic solid tumors with ≥ 2 prior lines of therapy (NCT05346484). CF33-hNIS is administered in 21-day cycles on C1D1 and C1D8, then D1 of each cycle thereafter. Pembrolizumab begins C2D1 for the combination groups and is administered Q3W. The co-primary endpoints are safety and to identify the recommended phase 2 dose. Secondary endpoints include objective response rate according to RECIST v1.1 and iRECIST, and to assess levels of viral replication via Single-Photon Emission Computerized Tomography (SPECT) with technetium-99. Results: As of Aug 2023, we report early results from seven patients with GI malignancies who received CF33-hNIS alone, including: colorectal cancer (3), bile duct (2), pancreatic (1) and hepatocellular carcinoma (1). The disease control rate is 86%. Notably one patient with cholangiocarcinoma, treated IT with 3.0x107 PFU, presented with pseudoprogression with a 49% increase in tumor burden after two cycles of therapy. By the 4th cycle they achieved a complete response (CR) with no known recurrence. A second patient with bile duct cancer, who previously progressed on checkpoint blockade therapy, achieved stable disease for &gt;5 months upon receiving IV-administered CF33-hNIS (3.0x107 PFU). Treatment-related adverse events for the CR patient included grade 1 fever and injection site reaction. All other patients experienced no treatment-related adverse events. SPECT analysis of the CR patient reveals intense levels of viral replication within the injected lesion and a concomitant increase in Th1 cytokines in cycle three that coordinated with tumor reduction. In-depth immunological changes in peripheral blood and on-treatment tumor biopsies will be presented. Conclusions: CF33-hNIS can replicate within cholangiocarcinoma lesions, as shown by SPECT imaging, and drive immunological changes known to promote antitumor immunity. CF33-hNIS monotherapy may be an effective and safe treatment option for GI malignancies, including cholangiocarcinoma, a rare disease with an unmet medical need. Treatment with CF33-hNIS monotherapy was well tolerated and the study has advanced to examine combination therapy with pembrolizumab. Clinical trial information: NCT05346484 .

Complete responses in AL amyloidosis are unequal: the impact of free light chain mass spectrometry in AL amyloidosis

AbstractAmyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry–based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

The predictive value of systemic immune-inflammatory markers before and after treatment for pathological complete response in patients undergoing neoadjuvant therapy for breast cancer: a retrospective study of 1994 patients.

Systemic immune-inflammatory markers have a certain predictive role in pathological complete response (pCR) after neoadjuvant treatment (NAT) in breast cancer. However, there is a lack of research exploring the predictive value of markers after treatment. This retrospective study collected data from 1994 breast cancer patients who underwent NAT. Relevant clinical and pathological characteristics were included, and pre- and post-treatment complete blood cell counts were evaluated to calculate four systemic immune-inflammatory markers: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII). The optimal cutoff values for these markers were determined using ROC curves, and patients were classified into high-value and low-value groups based on these cutoff values. Univariate and multivariate logistic regression analyses were conducted to analyze factors influencing pCR. The factors with independent predictive value were used to construct a nomogram. After NAT, 383 (19.2%) patients achieved pCR. The area under the ROC curve is generally larger for post-treatment markers compared to pre-treatment markers. Pre-treatment NLR and PLR, as well as post-treatment LMR and SII, were identified as independent predictive factors for pCR, along with Ki-67, clinical tumor stage, clinical lymph node stage, molecular subtype, and clinical response. Higher pre-NLR (OR = 1.320; 95% CI 1.016-1.716; P = 0.038), pre-PLR (OR = 1.474; 95% CI 1.058-2.052; P = 0.022), post-LMR (OR = 1.532; 95% CI 1.175-1.996; P = 0.002), and lower post-SII (OR = 0.596; 95% CI 0.429-0.827; P = 0.002) are associated with a higher likelihood of achieving pCR. The established nomogram had a good predictive performance with an area under the ROC curve of 0.754 (95% CI 0.674-0.835). Both pre- and post-treatment systemic immune-inflammatory markers have a significant predictive role in achieving pCR after NAT in breast cancer patients. Indeed, it is possible that post-treatment markers have stronger predictive ability compared to pre-treatment markers.

Assessment of novel prognostic biomarkers to predict pathological complete response in patients with non-metastatic triple-negative breast cancer using a window of opportunity design.

Triple-negative breast cancer (TNBC) includes approximately 20% of all breast cancer and is characterized by its aggressive nature, high recurrence rates, and visceral metastasis. Pathological complete response (pCR) is an established surrogate endpoint for survival. The window of opportunity studies provide valuable information on the disease biology prior to definitive treatment. To study the association of dynamic change in pathological, imagining, and genomic biomarkers that can prognosticate pCR. The study aims to develop a composite prognostic score. Clinical, interventional, and prognostic biomarker study using the novel window of opportunity design. The study aims to enroll 80 treatment-naïve, pathologically confirmed TNBC patients, administering a single dose of paclitaxel and carboplatin during the window period before neoadjuvant chemotherapy (NACT). Tumor tissue will be obtained through a tru-cut biopsy, and positron emission tomography and computed tomography scans will be performed for each patient at two time points aiming to evaluate biomarker alterations. This will be followed by the administration of standard dose-dense NACT containing anthracyclines and taxanes, with the study culminating in surgery to assess pCR. The study would develop a composite prognostic risk score derived from the dynamic change in the Ki-67, tumor-infiltrating lymphocytes, Standardized Uptake Value (SUV max), Standardized Uptake Value for lean body mass (SUL max), and gene expression level pre- and post-intervention during the window period prior to the start of definitive treatment. This outcome will aid in categorizing the disease biology into risk categories. The current study is approved by the Institutional Ethics Committee [Ethics: Protocol. no. JIP/IEC/2020/019]. This study was registered with ClinicalTrials.gov [CTRI Registration: CTRI/2022/06/043109]. The validated biomarker score will help to personalize NACT protocols in patients in TNBC planned for definitive treatment.

Pharmacoeconomic analysis of using empegfilgrastim for the treatment of early and locally advanced HER2+ breast cancer in the Russian Federation

Objective: to assess budget impact of using empegfilgrastim for the prevention of febrile neutropenia in patients with early and locally advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer who receive neoadjuvant “docetaxel / carboplatin / trastuzumab + pertuzumab” regimen, considering possible subsequent adjuvant therapy with trastuzumab emtansine or trastuzumab within the Russian healthcare system.Material and methods. We searched and analyzed published clinical, epidemiological and pharmacoeconomic studies as well as regulatory and legal documents. A decision tree model was constructed to reflect the probabilities of switching to different adjuvant therapy regimens depending on the achievement of pathomorphological complete response in patients with early and locally advanced HER2+ breast cancer. The budget impact analysis was carried out comparing two primary prophylactic options, empegfilgrastim and filgrastim.Results. Despite the higher costs of prevention with empegfilgrastim compared to filgrastim (249 vs. 134 thousand rubles), due to the higher rate of achieving a pathomorphological complete response and, accordingly, fewer cases requiring adjuvant therapy with the more expensive trastuzumab emtanzine, savings of 916 thousand rubles per 1 patient per 1 year of therapy are possible. In general, prophylaxis in the target population diagnosed with early and locally advanced HER2+ breast cancer using empegfilgrastim will result in a cost reduction of 9.4 billion rubles per 1 year compared to filgrastim.Conclusion. Empegfilgrastim prophylaxis, despite its higher annual cost, is an efficient option within the Russian healthcare system. In addition to reducing the incidence of febrile neutropenia, the frequency and dose of chemotherapy are preserved, resulting in increased efficacy of the primary therapy.

Development and validation of a nomogram to predict pathological complete response in patients with locally advanced gastric adenocarcinoma treated with neoadjuvant chemotherapy in combination with PD-1 antibodies.

Currently, the survival benefits of combining neoadjuvant chemotherapy with programmed death 1 (PD-1) antibody immunotherapy in advanced gastric adenocarcinoma remain controversial. Emerging evidence suggests that the survival benefits of neoadjuvant therapy in advanced gastric adenocarcinoma hinge upon the attainment of pathological complete response (pCR). Therefore, the prediction of pCR in patients undergoing neoadjuvant chemotherapy combined with PD-1 antibody immunotherapy holds significant importance and is beneficial for the individualized treatment of gastric cancer (GC) patients. Clinical and pathological characteristics of patients with GC who received neoadjuvant chemotherapy combined with PD-1 inhibitor (camrelizumab) therapy and radical gastrectomy between January 2019 and December 2020 at the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital were retrospectively analyzed. A total of 52 patients were enrolled in the study, with all subjects assigned to the training set. The neoadjuvant regimen consisted of a combination of PD-1 inhibitor and fluorouracil analogues plus oxaliplatin, comprising two drugs. The patients were divided into a pCR group and a non-pCR group according to pCR occurrence. Multifactor logistic regression analysis was applied to determine the correlation between each factor and pCR. A prediction model was developed based on the results of the logistic regression analysis. The predictive performance of the model was evaluated using the receiver operating characteristic curves. Internal verification was completed via the bootstrapping method. The pCR was observed in 10 out of 52 patients (19.2%). The results of binary logistic regression multivariate analysis showed that cN stage [odds ratio (OR): 0.215; P=0.03], combined positive score (CPS) (OR: 6.364; P=0.026), and tumor diameter (OR: 0.112; P=0.026) were independent predictors of pCR. The nomogram prediction model for the pCR was plotted with a concordance index of 0.923 [95% confidence interval (CI): 0.8441-1]. Neoadjuvant chemotherapy combined with PD-1 antibodies may be the preferred option for patients with advanced gastric adenocarcinoma who have a small tumor diameter, no or few lymph node metastases, and high CPS. The presented nomogram model exhibits the potential to predict pCR in advanced gastric adenocarcinoma patients, showcasing satisfactory predictive performance and potentially facilitating the implementation of personalized treatment strategies.

Early Complete Responses with Mosunetuzumab Monotherapy in Treatment-Naïve Follicular and Marginal Zone Lymphomas with Only Low-Grade Cytokine Release Syndrome

Introduction Mosunetuzumab (mosun) is a CD20xCD3 bispecific antibody that has been FDA-approved for relapsed/refractory follicular lymphoma after two prior lines of therapy. Updated follow up of the pivotal study in relapsed/refractory patents (Sehn et al ICML 2023, median follow up 28.3 months) showed a CR rate of 60%. Among the patients in CR, 77% remained alive and progression free at 2 years. We hypothesized that mosun would be even more active in patients (pts) without prior lymphotoxic therapy. Therefore, we designed a response adapted study for pts with untreated follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods This is a single center, open label, investigator-initiated response-adapted clinical trial in untreated pts with FL or MZL with indication for treatment. Pts received subcutaneous mosunetuzumab monotherapy for 8 cycles (21 day cycle, Part A) employing step up dosing in cycle 1 (5 mg, 45 mg, 45 mg). Dexamethasone prophylaxis was administered through C2D1, and could be omitted after that for patients without CRS in the previous cycle. A PET/CT was performed after 8 cycles, and pts in CR were observed without further treatment. Pts with SD or PR could receive 6 cycles (21 day cycle, Part B) of polatuzumab vedotin and obinutuzumab, followed by an end of treatment (EOT) PET/CT. Total planned accrual is 42 pts. The primary endpoint is complete response (CR) rate. A pre-planned interim efficacy analysis is being reported after 20 enrolled pts. If 14 or fewer of the first 20 subjects do not achieve an objective response, the study will be suspended to enrollment. Additional planned safety analyses are in place with suspension rules to detect excessive G4 non-heme toxicity and G2+ CRS. Results 26 pts enrolled on study between March 24, 2022, and March 11, 2023, with 26 pts evaluable for safety, and 21 pts are evaluable for efficacy. Median age was 64 (42-83), including 16 (62%) age 60+. Histologies enrolled include G1-2 follicular lymphoma (19, 73%), G3A follicular lymphoma (4, 15%), and marginal zone lymphoma (3, 12%). The most common indication for treatment was symptomatic disease (19, 73%). All treatment was delivered as an outpatient. Three pts experienced a serious adverse event (one pt with G3 lung infection followed by G3 shingles, one pt observed overnight with G1 cytokine release syndrome, and one pt with a G2 URI). Other G3 non-lab AEs observed were diarrhea (1, 4%), syncope (1, 4%), and hypertension (1, 4%). Sixteen (62%) pts experienced G1 CRS, with no G2 or higher CRS observed or any grade ICANS observed. No pts required tocilizumab. All CRS events first occurred during cycle 1. Headache was common but low grade (G1 14, 54%, G2 1, 4%). Heme toxicity &amp;gt; G1 was uncommon, with G4 neutropenia (1, 4%), and G2+ thrombocytopenia (2, 8%). No G4 non-heme toxicity was observed. Nearly all pts (92%) experienced at least one injection site reaction, which were all G1 except a single pt with a G2 reaction. Seven (26%) pts experienced a treatment delay due to toxicity, primarily due to infection in 4 pts. Only one patient did not receive all doses of mosun - G3 ALT increase and prolonged G1 CRS led to discontinuation after cycle 1 (patient achieved CR). Twenty-one patients are efficacy evaluable, with an overall response rate (ORR) of 100%. Eighteen patients have completed mosun therapy, with an ORR and CR rate of 100% and 83%, respectively. Three patients proceeded to obinutuzumab and polatuzumab combination therapy, of whom two have completed all treatment (both converted to CR). All pts remain alive and progression-free. Updated data will be presented at the meeting. Conclusion Fixed duration mosun monotherapy achieves a high CR rate in untreated pts with follicular and marginal zone lymphoma with no G2+ CRS and no ICANS of any grade. Injection site reactions and headaches were common but reversible. Safety and efficacy has remained well within study suspension thresholds and accrual is ongoing to a goal of 42 total patients.

Rituximab Ibrutinib Lenalidomide (R2I) Combination for Primary or Secondary Large B-Cell CNS Lymphoma: Last Resort or Bridge to Cellular Therapy?

Background: Primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL) each carry a poor prognosis. About 50% of patients with PCNSL will have refractory or relapsed disease correlating with dismal survival. SCNSL is associated with median overall survival (OS) of &amp;lt;6 months. (El-Galaly et al . Eur. J. Cancer 2018) Lenalidomide and ibrutinib each have single agent activity in PCNSL and SCNSL, albeit with limited duration of response (DOR). In combination, they have synergistic activity through modulation of NF-kappa B pathway. The regimen rituximab, lenalidomide, and ibrutinib (R2I) has demonstrated complete and durable responses in a subset of patients with good tolerability. (Houllier et al . Neurology 2021). We report our institutional outcomes with this regimen and its potential role as a bridge to autologous stem cell transplantation (ASCT) or CD19-targeted CAR T-cell therapy. Methods: This retrospective study included ten large B-cell lymphoma (LBCL) patients with PCNSL or SCNSL who received R2I regimen at Miami Cancer Institute from December 2020 to March 2023. Treatment response was assessed using International PCNSL Collaborative Group's criteria. (Abrey et al. J Clin Oncol 2005) Efficacy was evaluated from the start of R2I regimen. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: The median age at R2I initiation was 71 (range, 57-85) years. Six of 10 (60%) patients were ≥65 years. Five of 10 (50%) patients had PCNSL. The median number of prior lines of therapy was 2 (range, 1-7). None of the patients had prior ASCT. The median number of cycles of R2I was 4 (range, 1-23). Four patients received a higher dose of rituximab (500mg/m 2). Overall response rates (ORR) and complete response (CR) rates were 80% (95% CI, 55.2 to 100) and 40% (95% CI, 9.6 to 70.3), respectively. The median time to best response was 1.5 (range, 1.0-13.0) months and the median DOR was 5.5 (range, 2.5-18.0) months. The 1-year PFS and OS were 38.8% (95% CI: 4.9 to 72.8) and 56% (95% CI: 22.5 to 89.4), respectively (Figure 1). In the PCNSL subgroup, the 1-year OS was 80% (95% CI, 44.9 to 100) and PFS was 60% (95% CI, 17 to 100). No differences in response rates to R2I between PCNSL and SCNSL were observed (p=0.9). There were no deaths or treatment discontinuations due to R2I toxicity. Two patients on R2I underwent subsequent cellular therapy. One PCNSL patient in CR received carmustine (BCNU) and thiotepa conditioning followed by autograft rescue and remains in remission 16 months post-ASCT. The second patient received CD19-targeted CAR T-cell therapy with axicabtagene ciloleucel for SCNSL. The patient expired 119 days after CAR T-cell therapy due to systemic disease relapse. Another patient, initially deemed ineligible for any cellular therapy due to poor performance status, has achieved a durable response with improvement of performance status and is currently awaiting ASCT. Conclusion: R2I is an effective and safe regimen in patients with PCNSL and SCNSL. Although responses without consolidation may be durable, R2I should be considered as an active drug combination and well-tolerated bridge to cellular therapy to achieve long term survival.

Split scar sign to predict complete response in rectal cancer after neoadjuvant chemoradiotherapy: systematic review and meta-analysis

ObjectivesMagnetic resonance imaging (MRI) is the modality of choice for rectal cancer initial staging and restaging after neoadjuvant chemoradiation. Our objective was to perform a meta-analysis of the diagnostic performance of the split scar sign (SSS) on rectal MRI in predicting complete response after neoadjuvant therapy.MethodsMEDLINE, EMBASE, and Cochrane databases were searched for relevant published studies through June 2023. Primary studies met eligibility criteria if they evaluated the diagnostic performance of the SSS to predict complete response on pathology or clinical follow-up in patients undergoing neoadjuvant chemoradiation. A meta-analysis with a random-effects model was used to estimate pooled sensitivity and specificity, area under the curve (AUC), and diagnostic odds ratio (DOR) of the SSS.ResultsA total of 4 studies comprising 377 patients met the inclusion criteria. The prevalence of complete response in the studies was 21.7–52.5%. The pooled sensitivity and specificity of the SSS to predict complete response were 62.0% (95% CI, 43.5–78.5%) and 91.9% (95% CI, 78.9–97.2%), respectively. The estimated AUC for SSS was 0.83 (95% CI, 0.56–0.94) with a DOR of 18.8 (95% CI, 3.65–96.5).ConclusionThe presence of SSS on rectal MRI demonstrated high specificity for complete response in patients with rectal cancer after neoadjuvant chemoradiation. This imaging pattern can be a valuable tool to identify potential candidates for organ-sparing treatment and surveillance.Clinical relevance statementSSS presents high specificity for complete response post-neoadjuvant. This MRI finding enhances rectal cancer treatment assessment and aids clinicians and patients in choosing watch-and-wait over immediate surgery, which can potentially reduce costs and associated morbidity.Key Points•Fifteen to 50% of rectal cancer patients achieve complete response after neoadjuvant chemoradiation and may be eligible for a watch-and-wait strategy.•The split scar sign has high specificity for a complete response.•This imaging finding is valuable to select candidates for organ-sparing management.

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer

ABSTRACT Based upon results of the KEYNOTE-522 trial and following approval by regulatory authorities, the addition of pembrolizumab to chemotherapy is now the standard-of-care for the treatment of early triple-negative breast cancer (eTNBC) (Clinical stage II-III). Pembrolizumab is a programmed cell death protein 1 monoclonal antibody, known to cause immune-related adverse events (irAEs) in a significant subset of patients. Real-world data on incidence, type and treatment strategies of irAEs in the setting of eTNBC treatment are sparse. In this multicenterretrospective analysis, we characterized real-world incidence of irAEs and treatment outcomes such as pathological complete response (pCR) from the combination of pembrolizumab and chemotherapy as neoadjuvant treatment for eTNBC. We found a rate of irAEs of all grades of 63.9% and of 20% for irAEs of grade 3 or higher. In the overall population, a pCR rate of 57.1% was observed. The emergence of irAEs correlated significantly with pCR (72.2% versus 30.8%; p =.03). Discontinuation of neoadjuvant chemotherapy before week 12 correlated significantly with a lower pCR rate. To our knowledge, this is the first study evaluating the real-world efficacy and safety of a neoadjuvant combination of chemotherapy and pembrolizumab in eTNBC, demonstrating a significant correlation between irAEs and pCR. Early discontinuation of neoadjuvant therapy due to AEs resulted in a lower pCR rate.

Real-Life Experience of the Combination of Daratumumab, Bortezomib, Melphalan, and Prednisone (DVMP) in Patients with Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem-Cell Transplantation

INTRODUCTION The combination of daratumumab, bortezomib, melphalan, and prednisone (D-VMP) is an effective and safe alternative treatment for patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous hematopoietic stem-cell transplantation (HSCT) as described in ALCYONE clinical trial. However, real-life data is limited. This study aims to evaluate the data derived from real-life experience with this combination. METHODS This is a Spanish retrospective, multicenter study. One hundred eleven adults with NDMM ineligible for autologous HSCT who had started first-line treatment with D-VMP from 01/Jun/2019 to 01/Apr/2023 were included. The primary endpoint was to describe the progression-free survival (PFS), and the secondary endpoints were to describe overall response rate (ORR), very good partial response (VGPR), complete response (CR), overall survival (OS), and safety profile. RESULTS A total of 111 patients were included, 57 (51%) were males. The median age was 77 years (IQR 73-82), with 67% ≥ 75 years. Seven percent had an ECOG &amp;gt;2, 6% severe anemia (Hb &amp;lt;7.5g/dL), 14% creatinine &amp;gt;2mg/dL, and 7% had a first in-hospital dialysis. Twenty-one (19%) had R-ISS III disease stage, and 22 (20%) had extramedullary disease (16% bone-related plasmacytomas and 4% soft-tissue plasmacytomas). Of the 95 patients evaluable for cytogenetics, 13 (14%) had t(11;14), 36 (38%) had at least one poor-prognosis cytogenetic abnormality (del17p, t(4;14), t(14;16), gan/amp(1q) or del(1p)), and 10 (10%) had &amp;gt; 1. Of all patients, 83 (75%) had completed induction, with a median number of cycles of 9 (IQR 6-9). Among these patients, 26 (23%) received combined maintenance with daratumumab and bortezomib. The ORR was 91%, with at least VGPR in 66% of patients. The ORR and VGPR/CR rates were consistent regardless of age (ORR &amp;gt;74 years 86% vs &amp;lt;75 years 92%; VGPR/CR &amp;gt;74 years 67% vs &amp;lt;75 years 62%) and cytogenetic risk (ORR high-risk cytogenetic 86% vs standard cytogenetic 94%; VGPR/CR high risk cytogenetic 64% vs standard cytogenetic 68%). The median time to response was 35 days (IQR 24-49), and the median time to best response was 206 days (IQR 91-458). Minimal residual disease (MRD) was determined in 27 (54%) of patients in CR and 6 (26%) in VGPR. Eighteen patients in CR and 1 patient in VGPR had negative MRD (at least 10 -4). Twelve patients with negative MRD were subsequently re-evaluated, and 7 maintained MRD negativity at 4 (1), 6 (2), 9 (2), 12 (1) and 24 (1) months. Median OS was 44 months (95% confidence interval [CI], 33 to 55) and median PFS was 28 months (95% CI, 21 to 36). At a median follow-up of 22,6 months (IQR 15-30), the 36-month OS rate was 60% (95% CI, 52 to 68). Median OS was 36 months (95% CI 24 to 45) in the high cytogenetic risk group. Median PFS was 22 months(IC 95% 7 to 38) in the high cytogenetic risk group and 9 months (IC 95% 0 to 22) in the group with &amp;gt; 1 poor-prognosis cytogenetic abnormality. The dose of bortezomib was reduced in 42% of patients, mainly due to neuropathy (42%). The dose of melphalan was reduced in 28%, mainly because of myelotoxicity (29%) and kidney failure (19%). Both bortezomib and melphalan were discontinued in 6% of patients. Daratumumab did not require adjustment or early suspension. There were 13 deaths (12%), 4 due to progression, 4 due to infection, and 5 due to a cause unrelated to the MM. Among 24 (22%) of total patients who experienced relapse, 96% received subsequent therapy. The most frequent therapy was Lenalidomide-Dexamethasone (46%) followed by Carfilzomib-Lenalidomide-Dexamethasone (38%). CONCLUSIONS In real-life practice, D-VMP combination in patients with NDMM ineligible for transplant showed comparable efficacy and safety profile with those reported in ALCYONE clinical trial. Although the PFS and OS data are lower than those reported in ALCYONE, this could be due to the older age and a worse clinical involvement of the patients included in this study.

Odronextamab Demonstrates Durable Complete Responses in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Progressing after CAR-T Therapy: Outcomes from the ELM-1 Study

Background Chimeric antigen receptor (CAR) T-cell therapies have recently been established as an important option for the management of relapsed/refractory (R/R) DLBCL. However, real-world studies suggest that approximately half of all patients (pts) receiving commercial CAR-T therapies will relapse within 6 months. These pts have a poor prognosis, with estimated overall survival (OS) of only 5 months, indicating a significant unmet need. Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated activity in both R/R follicular lymphoma and R/R DLBCL. We have previously reported encouraging results with odronextamab from the Phase 1 ELM-1 study (NCT02290951) in pts with R/R DLBCL post CAR-T therapy (Bannerji R, et al. Lancet Haematol. 2022). These results were consistent with the antitumor activity seen in pts with R/R DLBCL from the Phase 2 ELM-2 study (Kim WS, et al. ASH 2022). Here, we present an updated analysis of outcomes in a prespecified cohort of post CAR-T patients from ELM-1. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Revisions to the step-up regimen were reported previously (Bannerji R, et al. Lancet Haematol. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 160 mg on Days (D) 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Those pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing with 320 mg every 4 weeks. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DoR), progression-free survival (PFS), and OS. Immune biomarker assessment was an exploratory endpoint. Results As of Dec 20, 2022, 46 pts were treated (safety-evaluable), with 44 pts evaluable for efficacy. For safety-evaluable pts, median age was 63 years (range 27-82), 67% male, 74% Ann Arbor stage III-IV, and 72% were refractory to CAR-T therapy administered in any prior line. 44 pts were evaluable for efficacy after 4.9 months median duration of follow-up. The ORR and CR rate by ICR were 48% (21/44) and 30% (13/44), respectively. Responses were durable, and both median DoR and median duration of CR were not reached. The probability of maintaining a response for 12 months was 62% and the probability of maintaining a CR for 9 months was 86%.A responder analysis of the subgroup of pts who achieved a CR will be presented. The CAR-T treated pts with DLBCL who were evaluable for biomarker analysis (n=10) had lower T-cell counts at baseline compared with CAR-T naive DLBCL pts (n=41 comparable pts who received odronextamab in ELM-2), yet the fold-change of T-cell expansion at C4D15 was greater in CAR-T treated pts versus CAR-T naive pts. T-cell dynamics, such as changes in activation, exhaustion, and memory subsets, will be presented. Safety was generally consistent with that previously reported. Six (13%) pts permanently discontinued odronextamab due to a treatment-emergent AE (device-related infection, pneumonia, dysphagia, gait disturbance, leukemia, and encephalopathy [n=1 each]). The most common treatment-emergent AE was CRS (any grade, 52%). The highest grade of CRS reported was Grade 2, and low-grade CRS events occurred in 46% of pts with the 0.7/4/20 mg step-up regimen. No cases of ICANS were reported in pts with the 0.7/4/20 mg regimen. Grade ≥3 infections occurred in 10 (22%) pts, with no Grade 5 events. No cases of tumor flare were reported. Conclusions Odronextamab monotherapy demonstrates encouraging antitumor activity in heavily pretreated pts who have progressed after CAR-T therapy, with a generally manageable safety profile. Durable CRs were achieved in this difficult-to-treat setting. These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience

Allogeneic Stem Cell Transplantation for Relapsed and/or Refractory Hodgkin Lymphoma: A Multicenter Real World Experience Introduction Relapsed and/or refractory (R/R) Hodgkin Lymphoma (HL) after autologous stem cell transplant (SCT) is associated with poor outcomes and nearly 50% of patients will ultimately relapse. Novel therapeutic agents such as checkpoint inhibitors (CPIs) (nivolumab, pembrolizumab) and brentuximab vedotin (BV) have both shown considerable activity in this patient population, but allogeneic SCT (alloSCT) maintains its curative potential also in the era of new drugs. Herein we report on our multicenter experience with alloSCT for R/R HL. Methods Seventy patients with R/R classic HL who underwent alloSCT between 2004 and 2021 in three transplant centers were included. Patients were included between 2004-2010 (era1) in one centre, 2011-2021 (era2) in all centers. Disease response was evaluated according to Lugano classification. Primary end point was post transplant (tx) overall response rate (ORR). Secondary endpoints were overall survival (OS), progression free survival (PFS), non relapse mortality (NRM) and response rates according to parameters especially tx years, and pre/post tx CPIs and/or BV usage. Results Patient characteristics are summarized in the Table. Median follow up time after alloSCT was 64 months (range, 40.7-87.3). Post tx disease relapse or progression occurred in 23 patients (33%). The median time to disease relapse was 6.3 months (range, 1-24.5). Twenty nine patients were alive at the analytic date (41%); 23 in complete response (CR) (79%), 4 partial response (PR) (14%), 2 stabl disease (SD) (7%). The 3-year OS, PFS were 39% (95% CI 27.2-50.8) and 28% (95% CI 16.2-39.8), respectively; the day 100 and 1-year NRM rates were 26% (95% 16.2-35.8) and 37% (95% CI 25.2- 48.8), respectively. According to the tx year, the pre tx response rates were not statistically different between the two eras (p=0.46) but post tx CR rates were significantly higher in era2 (p=0.01). The survival (OS, PFS) analysis and NRM rates demonstrated no difference between both eras, but the PFS was significantly longer in 2016 and after (p=0.03). Patients who received alloSCT between era 1 and era 2 in one and only centre; the survival rates, and NRM were similar across the two eras. The patients with chemosensitive disease (CR, PR) at the time of alloSCT had more common pre tx BV usage (p=0.03), RIC conditioning regimen (p=0.002), and were with high HCT CI score (p=0.02), while the low proportion of ATG usage (p=0.02). Achievement of a CR at pre tx associated with better OS, PFS, and NRM. Patients in CR at the time of the post tx was associated with significantly improved OS and PFS (p&amp;lt;0.05). Patients who received BV and CPIs at any point pre and post tx had better OS, PFS and the NRM was low, but not statistically significant. There was a lower NRM rates in the post tx BV (p=0.06) and CPIs (p=0.08) usage. Regarding to post tx cyclophosphamide (cy) versus ATG usage; patients who received ATG had signicantly shorter OS (p=0.04), an increase in NRM (p=0.01), but similar PFS (p=0.28) compared with those who did not. Patients who received post tx cy had signicantly better OS (p=0.04) and PFS (p=0.05) but similar NRM (p=0.19) compared with those who did not. There was no statistically significant difference in OS, PFS and NRM with regard to the conditioning regimens (RIC and MAC) (p&amp;gt;0.05). Regarding donor type; the use of pre tx CPIs, TBI in conditioning regimen, and post cy were common for haploidentical (haplo) tx (p&amp;lt;0.05). ATG was used more commonly for matched/mismatched unrelated donor (MUD/MMUD) when compared with matched related donor (MRD) (p&amp;lt;0.001). The incidence of acute graft versus host disease (GVHD) (p=0.09) and chronic GVHD (p=0.002) were higher in patients who received MRD grafts when compared with MUD/MMUD and haplo. Haplo donors had significant better OS (p=0.015) and PFS (p=0.03) compared with MUD/MMUD and MRD. There was a significantly higher NRM in the MUD/MMUD compared with others (p&amp;lt;0.05). Conclusions Our results suggest that alloSCT continues to play an important therapeutic role for patients with R/R cHL. The improved outcomes of alloSCT in HL over time, probably due to general improvements in supportive care, a better selection of patients and the arrival of novel therapeutic therapies. The efficacy of alloSCT can be determined by multicenter prospective studies in selected patient groups.

Multi-Center Clinical Validation of a Mass Spectrometry Immunoassay for the Diagnosis and Monitoring of Multiple Myeloma and Associated Disorders

Introduction: Mass spectrometry (MS) technology holds great promise for the investigation of monoclonal proteins (M proteins) in peripheral blood. We present results from a multi-center clinical validation study using quantitative immunoprecipitation MS (QIP-MS). QIP-MS combines isotype-specific immunopurification with matrix-assisted laser-desorption ionization MS, and offers automated, sensitive detection, isotyping and quantification of M proteins. It reports the mass/charge ratio (m/z) of the involved light chain, which serves as molecular fingerprint for monitoring the M protein. Methods: The study included 460 diagnosed monoclonal gammopathy (MG) patients (160 multiple myeloma (MM), 112 smoldering MM (SMM), 120 monoclonal gammopathy of undetermined significance (MGUS), 47 Waldenström's Macroglobulinemia (WM), and 21 AL amyloidosis), and 170 disease controls for assessing diagnostic sensitivity and specificity. Sixty-four MM patients with 439 follow-up samples and 10 WM patients with 91 follow-up samples were included to evaluate the ability of QIP-MS to detect M protein changes related to treatment. Median follow up was 19 and 15 months, respectively. Serum samples were retrospectively analyzed at three sites. QIP-MS was carried out using the automated EXENT® solution (in development, The Binding Site, part of Thermo Fisher Scientific). The assay's diagnostic sensitivity and specificity were calculated based on categorizing results as positive or negative. A positive result was defined in baseline samples as the presence of an M protein which was either an intact immunoglobulin ≥0.200 g/L or a light chain only. Results by QIP-MS were also compared to serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE). QIP-MS response categories were defined based on M protein changes per international guidelines criteria, and compared to response categories assigned by the treating physician. Complete response (CR) was defined as absence of the M-peak that was observed at baseline, using isotype and m/z value of ±4 as criterion for identity. Results: The overall diagnostic sensitivity of QIP-MS in this study was 95.0%: 93.3% for MGUS; 100.0% for SMM; 94.4% for MM; 100.0% for WM; and 71.4% for AL amyloidosis. The diagnostic specificity of the assay was 68.2%. QIP-MS identified an M protein in more MG patients compared to SPE: 437 (95.0%) vs 398 (86.5%). The positivity rate by QIP-MS vs SPE was 93.3% vs 84.2% in MGUS; 100% vs 92.9% in SMM; 94.3% vs 85.0% in MM; 100% vs 100% in WM and 71.4% vs 47.6% in AL amyloidosis. Method comparison demonstrated a Passing-Bablok slope of 0.8 to 1.2 between QIP-MS and SPE for the quantification of M proteins for each disease group and for each isotype, except for monoclonal IgM and in WM (slope of 1.58). In SPE-positive MG patients, the overall concordance between QIP-MS and IFE for M protein isotype was 97%. The overall concordance rate between QIP-MS response categories and standard response assignment was 55% for MM and 56% for WM: 48% for progressive disease (PD); 63% for stable disease (SD); 46% for minimal response (MR); 71% for partial response (PR); 66% for very good partial response (VGPR); and 25% for CR in MM patients. Among 73 responses categorized as CR, QIP-MS produced a positive result for the original clone in 55 (75.3%) cases. Concordance rates in WM patients were 71% for PD%; 30% for SD; 38% for MR; and 74% for PR; no VGPR or CR were reported by either method. Conclusions: In this study, QIP-MS demonstrated the potential for same or superior diagnostic sensitivity compared to SPE, high concordance with IFE for the M protein isotype and good quantitative agreement with SPE measurements of the M proteins. It reported higher IgM values compared to SPE, likely due to reliance on turbidimetric immunoglobulin measurement for quantitations. Diagnostic specificity was impacted by the identification of minor M proteins, not detectable by SPE, and whose clinical significance requires further investigation. QIP-MS demonstrated “moderate” to “fair” agreement for response assignment in MM and WM, respectively, mostly due to the detection of residual M proteins in a significant proportion of patients in CR, in line with its enhanced analytical sensitivity. These data support the use of QIP-MS as an aid in the diagnosis and monitoring of MGs.

A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background: Autologous CD19 CAR T cell therapies have demonstrated favorable clinical responses in relapsed or refractory (R/R) diffuse large B-cell lymphomas (DLBCL), but only a subset of patients (pts) experience durable remissions. We hypothesized that the redundancy of CD28 and CD3ζ signaling in a CAR design incorporating all 3 CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) might negatively affect T cell differentiation and promote exhaustion. Therefore, we created a new CD19 CAR construct with calibrated CAR activation potential by mutating 2 of the 3 ITAMs, termed 1XX, and hypothesized that a 1XX CAR would afford durable responses at lower dose and fewer toxicities compared to CARs comprising 3 ITAMs. We previously presented the data from the dose-escalation portion of the phase I clinical trial of 19(T2)28z-1XX CAR T cells in DLBCL (Park J et al. ASH 2022). We have now completed accrual and report the updated results from both dose escalation and expansion portion of the study with a longer follow-up (NCT04464200). Methods: This is a single-center, phase I, dose-escalation and expansion trial of 19(T2)28z1XX CAR T cells in adult pts with R/R DLBCL conducted at Memorial Sloan Kettering Cancer Center. Pts received fludarabine and cyclophosphamide lymphodepleting chemotherapy followed by a single infusion of CAR T cells. There were 4 dose levels in the dose escalation cohort: dose level (DL) 1 (25x10 6), DL2 (50x10 6), DL3 (100x10 6) and DL4 (200x10 6 CAR T cells). The primary objective of the trial was to evaluate safety and tolerability and determine the recommended phase 2 dose. Key secondary objectives include assessment of overall response and complete response rates. Results: 28 pts have been enrolled and treated; 16 pts on the dose escalation and 12 pts on the dose expansion phase of the study. Median age was 62 (range, 48-86). 20 pts (71%) had primary refractory disease, 3 pts (11%) had prior autologous HSCT, and 2 pts (7%) had prior autologous CD19 CAR T therapy. In the dose-escalation phase (n=16), 15 pts experienced grade 1-2 CRS (94%) and no pt experienced ≥grade 3 CRS. Two pts (13%) experienced ICANS: 1 pt with grade 1 and 1 pt with grade 3 (Table 1). Eight pts received tocilizumab and 5 pts received corticosteroid. Complete response (CR) was observed in 11 of 16 pts (69%) and partial remission (PR) in 1 pt (6%) with overall response rate (ORR) of 75%. Responses were seen across all dose levels (Table 1). The lowest dose (DL1: 25x10 6) was selected for dose-expansion based on exposure-response analysis and 12 additional pts were treated at that dose level. In a pooled analysis of 16 pts who received DL1 dose (4 in dose escalation and 12 in dose expansion), 12 pts and 1 pt experienced grade 1-2 (75%) and grade 3 CRS (6%), respectively. Only 1 pt experienced ICANS (6%) at grade 3 (same pt who had grade 3 CRS), which was reversible and transient (Table 1). 11 pts received tocilizumab and 9 pts received corticosteroids. Twelve pts achieved CR (75%) and 2 pts (12%) PR with the best ORR of 87% (Table 1). A lower metabolic tumor volume (MTV) at screening but not at post-bridging was associated with a higher likelihood of achieving CR (p=0.039). With a median follow-up of 345 days (range, 33-1024), 4 pts experienced relapse (1 CR and 3 PR pts) and 16 pts have ongoing CR &amp;gt; 6 months (Figure 1). While CAR T cell persistence analysis is ongoing, 5 pts have CAR T cells detected beyond one year in ongoing CR including a patient treated at DL1 with detectable CAR T cells at 2 years. Conclusions: Treatment with 19(T2)28z1XX CAR T cells was shown to be safe with durable remissions with low rates of severe CRS (4%) and ICANS (7%). The overall CR rate of 71% is encouraging and appears durable with the majority of CR patients in ongoing remission &amp;gt; 6 months at a median follow-up of 345 days and with persisting CAR T cells. With more patients treated at DL1 with a longer follow-up, the study demonstrates a high efficacy of 19(T2)28z1XX CAR T cells at a dose significantly lower (25x10 6) than those of approved CD19 CAR T cells (100-300x10 6) and support that the 1XX single ITAM signaling domain may lead to enhanced efficacy of CD19 CARs and allow infusion of a lower T cell dose with favorable toxicity profiles.

Novel Tumor Organoid-Based Mouse Model to Study Image Guided Radiation Therapy of Rectal Cancer After Noninvasive and Precise Endoscopic Implantation

PurposePreoperative (neoadjuvant) radiation therapy (RT) is an essential part of multimodal rectal cancer therapy. Recently, total neoadjuvant therapy (TNT) which combines simultaneous radio-chemotherapy with additional courses of chemotherapy (CTx) has emerged as an effective approach. TNT achieves a pathological complete remission in approximately 30% of resected patients, opening avenues for treatment strategies that avoid radical organ resection. Furthermore, recent studies have demonstrated that anti-PD-1 immunotherapy (IT) can induce clinical complete responses in patients with specific genetic alterations. Overall, there is significant potential to enhance outcomes through intensifying, personalizing, and de-escalating treatment approaches. However, the heterogeneous response rates to RT or TNT and strategies to sensitize patients without specific genetic changes to IT remain poorly understood. Materials and MethodsWe developed a novel orthotopic mouse model of rectal cancer which is based on precisely defined endoscopic injections of tumor organoids that reflect tumor heterogeneity. Subsequently, we employed endoscopic- and computed tomography-guided RT, and validated rectal tumor growth and response rates to therapy using small animal magnetic resonance imaging and endoscopic follow-up. ResultsRectal tumor formation was successfully induced in all mice following two organoid injections. Clinically relevant RT regimens with 5 × 5 Gy significantly delayed clinical signs of tumor progression and significantly improved survival. Consistent with human disease, rectal tumor progression correlated with the development of liver and lung metastases. Notably, longterm survivors after RT showed no evidence of tumor recurrence, as demonstrated by in vivo radiological tumor staging and histopathological examination. ConclusionsOur novel mouse model combines orthotopic tumor growth via non-invasive and precise rectal organoid injection and small animal RT. This model holds significant promise for investigating the impact of tumor cell-intrinsic aspects, genetic alterations of the host, or exogenous factors (e.g., nutrition or microbiota) on RT outcomes. Furthermore, it allows for the exploration of combination therapies involving CTx, IT or novel targeted therapies.