Regression Of Primary Tumor Research Articles

Comparative Analysis of Metastatic Thyroid Carcinoma versus Ectopic Thyroid Carcinoma in Lateral Neck Masses without Identifiable Primary Thyroid Carcinoma

Background/Objectives: Thyroid carcinoma, presenting as a lateral neck mass without an identifiable primary tumor within the thyroid, poses a diagnostic challenge. This comparative analysis aimed to explore the differences between metastatic thyroid carcinoma and ectopic thyroid carcinoma, as both present with a lateral neck mass without evidence of primary thyroid carcinoma. Methods: Searches were conducted for studies on thyroid carcinoma in the lateral neck without evidence of primary thyroid carcinoma. A total of 39 patients were identified from 32 reported studies. Results: Metastatic and ectopic thyroid carcinomas were found in 11 and 28 patients, respectively. Metastatic thyroid carcinoma is characterized by evidence of spontaneous primary tumor regression within the thyroid and commonly associated with multiple lymph node metastases in central and lateral neck compartments. Ectopic thyroid carcinoma is more commonly diagnosed in younger patients and is frequently identified in branchial cleft cysts. The coexistence of normal thyroid tissue adjacent to the ectopic thyroid carcinoma was confirmed, and patients with ectopic thyroid carcinoma exhibited significantly higher rates of second-stage thyroidectomy or neck dissection. When complete surgical excision was considered adequate, excision alone was chosen for patients with ectopic thyroid carcinoma. Conclusions: Identifying these differences is valuable for the differential diagnosis and development of treatment strategies for metastatic and ectopic thyroid carcinomas in lateral neck masses without evidence of primary thyroid tumor.

CD103+ cDC1 Dendritic Cell Vaccine Therapy for Osteosarcoma Lung Metastases.

We generated a CD103+DC vaccine using K7M3 OS cell lysates (cDCV) and investigated its ability to induce regression of primary tumors, established lung metastases, and a systemic immune response. A bilateral tumor model was used to assess cDCV therapy efficacy and systemic immunity induction. K7M3 cells were injected into mice bilaterally. Right-sided tumors received PBS (control) or cDCV. Left-sided tumors were untreated. Tumor growth was compared between the vaccine-treated and untreated tumor on the contralateral side and compared to the control group. The immune cell profiles of the tumors, and tumor-draining lymph nodes (TdLNs) and spleen were evaluated. To determine the efficacy of systemic cDCV therapy against established lung metastases, K7M3 cells were injected intratibially. Leg amputation was performed 5 weeks later. Mice were treated intravenously with PBS or cDCV and euthanized 6 weeks later. Lungs, TdLNs and spleen were collected. The number and size of the lung nodules were quantified. The immune cell profile of tumor, and lymph nodes and spleen were also evaluated. Using this same model, we evaluated the effect of cDCV + anti-CTLA-4. cDCV therapy inhibited the treated and untreated tumors and increased the number of T-cells in these tumors and the lymph nodes compared to control-treated mice. Systemic cDCV therapy administered following amputation decreased the size and number of lung metastases, and increased T-cell numbers in the tumor and lymph nodes. Combining anti-CTLA-4 with cDCV therapy increased cDCV efficacy against lung metastases. Intratumor cDCV generated a systemic immune response inhibiting the growth of both the treated and untreated tumors, with increased T-cells in the tumor and lymph nodes. Systemic cDCV was effective against established lung metastases. Efficacy was increased by anti-CTLA4. cDCVs may provide a novel therapeutic approach for relapsed/metastatic OS patients.

Factors influencing pathological complete response and tumor regression in neoadjuvant radiotherapy and chemotherapy for high-risk breast cancer

BackgroundPathological complete response (pCR) is a well-established prognostic factor in breast cancer treated with neoadjuvant systemic therapy (naST). The determining factors of pCR are known to be intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage as well as type of systemic therapy. The addition of neoadjuvant radiotherapy (naRT) to this paradigm might improve response, freedom from disease, toxicity and cosmetic outcome compared to adjuvant radiotherapy. The factors for pCR and primary tumor regression when neoadjuvant radiation therapy is added to chemotherapy have not been thoroughly described.MethodsWe performed a retrospective analysis of 341 patients (cT1-cT4/cN0-N+) treated with naRT and naST between 1990 and 2003. Patients underwent naRT to the breast and mostly to the supra-/infraclavicular lymph nodes combined with an electron or brachytherapy boost. NaST was given either sequentially or simultaneously to naRT using different regimens. We used the univariate and multivariate regression analysis to estimate the effect of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) as well as complete primary tumor response (ypT0/Tis; bpCR) in our cohort. Receiver operating characteristic (ROC) analysis was performed to evaluate the interval between radiotherapy (RT) and resection (Rx) as well as radiotherapy dose.ResultsOut of 341 patients, pCR and pbCR were achieved in 31% and 39%, respectively. pCR rate was influenced by resection type, breast cancer subtype, primary tumor stage and interval from radiation to surgery in the multivariate analysis. Univariate analysis of bpCR showed age, resection type, breast cancer subtype, clinical tumor stage and grading as significant factors. Resection type, subtype and clinical tumor stage remained significant in multivariate analysis. Radiation dose to the tumor and interval from radiation to surgery were not significant factors for pCR. However, when treatment factors were added to the model, a longer interval from radiotherapy to resection was a significant predictor for pCR.ConclusionsThe factors associated with pCR following naST and naRT are similar to known factors after naST alone. Longer interval to surgery might to be associated with higher pCR rates. Dose escalation beyond 60 Gy did not result in higher response rates.

Effect of preoperative immune checkpoint inhibitors on reducing residual lymph node metastases in patients with gastric cancer: a retrospective study

Objective: To investigate the effect of immune checkpoint inhibitors on reducing residual lymph node metastasis in patients with gastric cancer. Methods: The cohort of this retrospective study comprised patients from Nanfang Hospital of Southern Medical University and the First Affiliated Hospital of Xiamen University who had undergone systemic treatment prior to gastrectomy with D2 lymphadenectomy and had achieved Grade 1 primary tumor regression (TRG1) from January 2014 to December 2023. After exclusion of patients who had undergone preoperative radiotherapy, data of 58 patients (Nanfang Hospital: 46; First Affiliated Hospital of Xiamen University: 12) were analyzed. These patients were allocated to preoperative chemotherapy (Chemotherapy group, N=36 cases) and preoperative immunotherapy plus chemotherapy groups (Immunotherapy group, N=22 cases). There were no significant differences between these groups in sex, age, body mass index, diabetes, tumor location, pathological type, Lauren classification, tumor differentiation, pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, mismatch repair protein status, number of preoperative treatment cycles, or duration of preoperative treatment (all P>0.05). The primary outcome measure was postoperative lymph node downstaging. Secondary outcomes included postoperative depth of invasion by tumor, number of lymph nodes examined, and factors affecting residual lymph node metastasis status. Results: Lymph node downstaging was achieved significantly more often in the Immunotherapy group than the Chemotherapy group (pN0: 90.9% [20/22] vs. 61.1% [22/36]; pN1: 4.5% [1/22] vs. 36.1% [13/36]; pN2: 4.5% [1/22) vs. 0; pN3: 0 vs. 2.8% [1/36], Z=-2.315, P=0.021). There were no significant difference between the two groups in number of lymph nodes examined (40.5±16.3 vs. 40.8±17.5, t=0.076, P=0.940) or postoperative depth of invasion by primary tumor (pT1a: 50.0% [11/22] vs. 30.6% [11/36]; pT1b: 13.6% [3/22] vs. 19.4% [7/36]; pT2: 13.6% [3/22] vs. 13.9% [5/36]; pT3: 13.6% [3/22] vs. 25.0% [9/36]; pT4a: 9.1% [2/22] vs. 11.1% [4/36], Z=-1.331, P=0.183). Univariate analysis revealed that both preoperative treatment regimens were associated with residual lymph node metastasis status in patients whose primary tumor regression was TRG1 (χ2=6.070, P=0.014). Multivariate analysis incorporated the following factors: pretreatment depth of invasion by primary tumor, pretreatment lymph node stage, pretreatment clinical stage, number of preoperative treatment cycles, and preoperative treatment duration. We found that a combination of immunotherapy and chemotherapy administered preoperatively was an independent protective factor for reducing residual lymph node metastases in study patients whose primary tumor regression was TRG1 (OR=0.147, 95%CI: 0.026-0.828, P=0.030). Conclusion: Compared with preoperative chemotherapy alone, a combination of preoperative immunotherapy and chemotherapy achieved greater reduction of residual lymph node metastases in the study patients who achieved TRG1 tumor regression in their primary lesions.

NMR-Based Metabolomics of Blood Serum in Predicting Response to Induction Chemotherapy in Head and Neck Cancer-A Preliminary Approach.

The role of induction chemotherapy (iCHT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC) is still to be established due to high toxicity and variable response rates. The aim of this retrospective study is to use NMR-based serum metabolomics to predict the response rates to iCHT from the pretreatment samples. The studied group consisted of 46 LA-HNSCC patients treated with iCHT. The response to the treatment was evaluated by the clinical, fiberoptic, and radiological examinations made before and after iCHT. The proton nuclear magnetic resonance (1H NMR) serum spectra of the samples collected before iCHT were acquired with a 400 MHz spectrometer and were analyzed using multivariate and univariate statistical methods. A significant multivariate model was obtained only for the male patients. The treatment-responsive men with >75% primary tumor regression after iCHT showed pretreatment elevated levels of isoleucine, alanine, glycine, tyrosine, N-acetylcysteine, and the lipid compounds, as well as decreased levels of acetate, glutamate, formate, and ketone bodies compared to those who did not respond (regression of the primary tumor <75%). The results indicate that the nutritional status, capacity of the immune system, and the efficiency of metabolism related to protein synthesis may be prognostic factors for the response to induction chemotherapy in male HNSCC patients. However, larger studies are required that would validate the findings and could contribute to the development of more personalized treatment protocols for HNSCC patients.

Determinants of pathological complete response and tumor regression in high-risk breast cancer treated with neoadjuvant radiotherapy and chemotherapy.

e12652 Background: Pathological complete response (pCR) is a recognized prognostic indicator in breast cancer patients undergoing neoadjuvant systemic therapy (naST). Known determinants of pCR include intrinsic subtype, proliferation index, grading, clinical tumor and nodal stage, as well as the type of systemic therapy. Incorporating neoadjuvant radiotherapy (naRT) may enhance response rates, disease-free survival, toxicity profiles, and cosmetic outcomes compared to adjuvant radiotherapy. However, the factors influencing pCR and primary tumor regression with the addition of neoadjuvant radiotherapy to chemotherapy are not well-documented. Methods: A retrospective analysis was conducted on 341 patients (cT1-cT4/cN0-N+) who received naRT and neoadjuvant chemotherapy between 1990 and 2003. Treatment included naRT to the breast and, in most cases, to the supra-/infraclavicular lymph nodes, complemented by an electron or brachytherapy boost. NaST was administered either sequentially or concurrently with RT, utilizing various regimens. Univariate and multivariate regression analyses were employed to evaluate the impact of different subgroups and treatment modalities on pCR (ypT0/Tis and ypN0) and complete primary tumor response (ypT0/Tis). Receiver operating characteristic (ROC) analysis assessed the interval between radiotherapy (RT) and surgical resection (Rx), as well as the radiotherapy dose. Results: Out of 341 analyzed patients, 31.1% achieved pCR. Multivariate analysis revealed that pCR rates were affected by the planned type of resection, breast cancer subtype, primary tumor stage, and the interval between radiation and surgery. The biologically effective dose to the tumor did not significantly impact pCR. Univariate analysis identified age, resection type, breast cancer subtype, clinical tumor stage, and grading as significant factors for primary tumor regression. In the multivariate analysis, resection type, subtype, and clinical tumor stage remained significant. Radiation dose to the tumor and the interval from radiation to surgery were not significant for pCR. However, a longer interval from radiotherapy to resection significantly predicted pCR when treatment factors were included in the model. Conclusions: The factors associated with pCR following combined neoadjuvant chemotherapy and radiotherapy are akin to those identified with neoadjuvant chemotherapy alone. A prolonged interval to surgery may be linked to higher pCR rates. Escalating the dose beyond 60 Gy did not lead to increased response rates.

A phase 1 trial in progress for in situ immunomodulation with CDX-301, radiation therapy, poly-ICLC, and CDX-1140 in patients with unresectable and metastatic solid tumors.

TPS2697 Background: The prognosis for patients with unresectable and metastatic solid tumors that progress on standard of care therapy remains poor due to limited treatment options. Compelling evidence suggests that the induction and activation of tumor-residing conventional type-1 dendritic cells (cDC1) is critical to elicit anti-tumor immunity. Recently, we have demonstrated that a combinatorial regimen comprised of in situ delivery of Fms-like tyrosine kinase 3 ligand (Flt3L), radiation therapy (9Gy), and dual TLR3/CD40 stimulation 1) mobilizes cDC1 to the tumor microenvironment; 2) induces maturation of cDC1; 3) facilitates trafficking of cDC1 carrying tumor antigens to tumor-draining lymph nodes; 4) elicits de novo adaptive T cell immunity; 5) triggers regression of primary tumors, as well as non-irradiated distant tumors; and 6) develops tumor-specific systemic immunological memory using multiple syngeneic orthotopic murine models (1-4). Based on results from preclinical studies, we have initiated a phase 1 study as below. Methods: This is a phase 1 study of in situ immunomodulation with CDX-301 (Flt3L), radiation therapy, CDX-1140 and Poly-ICLC (dual CD40/TLR3 stimulation) in patients with unresectable and metastatic solid tumors. Eligibility for this study includes patients ≥ 18 yrs who have clinically or pathologically confirmed diagnosis of unresectable and metastatic melanoma, cutaneous squamous cell carcinoma, Merkel cell carcinoma, high-grade bone and soft tissue sarcoma or HER2/neu (-) breast cancer with no curative treatment options, and progressed on at least one line of standard systemic therapy. The unresectable disease to be irradiated and injected with medications must be located in breast, dermal, subcutaneous, or soft tissue, or lymph nodes with the longest axis of the tumor 2-7 cm, and should be considered safe for injection by the investigator. The metastatic disease must be measurable per irRECIST criteria. Patients will be treated with daily intratumoral injection of CDX-301 for 5 days (Day 1-5), radiation therapy (9Gy, Day 8) followed by administration of CDX-1140 and Poly-ICLC (Day 9). Up to 4 cycles of this combination therapy can be given every 3 weeks. The primary endpoints are safety/tolerability and to evaluate the MTD of for injection (intratumoral in the cohort A and intratumoral and intravenous in the cohort B) of CDX-1140. A standard 3+3 design, allowing for dose de-escalation, will be used within each cohort. Secondary endpoints are to evaluate immune signatures in blood and the tumor. This phase 1 trial opened to enrollment at the University of Southern California Norris Comprehensive Cancer Center in January 2023 (recruitment is currently 4 on February 6, 2024). 1. Nature Communications 2020. 2. J. Immunology 2021. 3. Cancer Research 2021. 4. Scientific Reports 2022. Clinical trial information: NCT04616248 .

Abstract 4027: From tumor progression to therapeutic control: Combinatorial targeting of immune vulnerabilities in TNBC

Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer, associated with limited treatment options and high mortality rates. Although immune checkpoint inhibitors (ICIs) show promise, early clinical results indicate benefits in only a specific subset of patients with TNBC. Preclinical evidence indicates that infiltrating macrophages contribute to breast tumor progression by restricting CD8+ T cell infiltration, activation, and cytotoxicity within tumor microenvironments. Preliminary data has revealed that immune-competent mammary tumor-bearing MMTV-PyMT transgenic mice have slowed tumor progression following sequential combination of a microtubule poison (paclitaxel; PTX) to enhance tumor immunogenicity, plus a macrophage-depleting/reprogramming agent such as a colony-stimulating factor 1 receptor blocking antibody (αCSF1R), and undergo primary tumor regression in 60% of transgenic mice when an ICI targeting PD-1 is applied (3x therapy) by a CD8+ T cell-dependent mechanism. Response to 3x therapy is associated with localized CD8+ T effector and resident memory cell expansion, and increased antigen-specific clonal expansion at primary tumor sites. We hypothesized that epigenetic plasticity was limiting T cell memory and thus impeding long-term tumor control. Using a class 1 benzamide histone deacetylase (HDAC) inhibitor (e.g., entinostat) sequentially added to PTX/αCSF1R/αPD-1 therapy (4x) resulted in primary tumor stasis in 100% of mice, and significantly enhanced overall survival, in two transgenic mouse models of breast cancer (MMTV-PyMT and C3-(1)-TAg). Cohorts were analyzed at distinct time points for primary and metastatic tumor burden, in addition to immunophenotyping (flow cytometry), transcriptional (bulk and scRNA-Seq), epigenetic (sciATAC-Seq), and T cell receptor (TCR) changes correlating with 4x responses. Improved outcome and tumor stasis was associated with increased presence of long-lived central and stem-like memory CD8+ T cell infiltration, intra-tumoral B memory cell, and CD4+ T follicular helper cell infiltration. Tumor stasis was achieved by B and T cell-dependent mechanisms where B cell depletion led to decreased T cell cytotoxicity. Adoptive serum transfer (AST) from 4x-treated MMTV-PyMT mice into either 3x-treated or untreated MMTV-PyMT mice elicited tumor stasis and control. These preclinical studies indicate the complexity of myeloid, B cell and T cell interactions that are co-opted by tumors, and identify novel paths to therapeutic tumor control by targeting vulnerable immune communication programs. Citation Format: Amanda Poissonnier, Eivind Valen Egeland, Wesley Horton, Shamilene Sivagnanam, Orian Stapleton, Rossin Erbe, Nell Kirchberger, Konjit Betre, Alyza Skaist, Ludmila Danilova, Andrew Fields, Peter Ordentlich, Andrew C. Adey, Elana J. Fertig, Lisa M. Coussens. From tumor progression to therapeutic control: Combinatorial targeting of immune vulnerabilities in TNBC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4027.

Design of a single-center, phase II trial to explore the efficacy and safety of 'R-ISV-RO'treatment in advanced tumors.

Background: The authors' preclinical study has confirmed that ROadjuvant (composed of TLR 7 agonists [imiquimod/R837]and OX40 agonists)injected into local lesions induces the regression of both primary tumor and distant metastasis. The authors propose to realize local control and exert abscopal effect through an 'R-ISV-RO' in situ strategy plus anti-PD-1 monoclonal antibody in advanced tumors. Methods: This study is a single-center, exploratory, phase II trial to evaluate the efficacy and safety of R-ISV-RO plus anti-PD-1 monoclonal antibody in advanced tumors. 30 patients with one or more measurable extracerebral lesions that are accessible for radiation or injection will be enrolled. The primary endpoint is the objective response rate of target lesions. Discussion/Conclusion: The efficacy and safety of the novel strategy will be further validated through this clinical trial.Clinical trial registration: ChiCTR2100053870 (www.chictr.org.cn/).

Accurately Controlled Tumor Temperature with Silica-Coated Gold Nanorods for Optimal Immune Checkpoint Blockade Therapy.

Photothermal therapy (PTT) at mild temperatures ranging from 44 to 45 °C holds tremendous promise as a strategy for inducing potent immunogenic cell death (ICD) within tumor tissues, which can reverse the immunosuppressive tumor microenvironment (ITM) into an immune-responsive milieu. However, accurately and precisely controlling the tumor temperature remains a formidable challenge. Here, we report the precision photothermal immunotherapy by using silica-coated gold nanorods (AuNR@SiO2), and investigating the optimal administration routes and treatment protocols, which enabled to achieve the sustained and controlled mild heating within the tumor tissues. First, the highest photothermal performance of AuNR@SiO2 with 20-nm silica shell thickness than 5 or 40 nm was confirmed invitro and invivo. Then, the optimal conditions for precision immunotherapy were further investigated to produce mild temperature (44 to 45 °C) accurately in tumor tissues. The optimal conditions with AuNR@SiO2 result in a distinct cell death with high early/late apoptosis and low necrosis, leading to very efficient ICD compared to lower or higher temperatures. In colon tumor-bearing mice, intratumorally injected AuNR@SiO2 efficiently promotes a mild temperature within the tumor tissues by local irradiation of near-infrared (NIR) laser. This mild PTT substantially increases the population of mature dendritic cells (DCs) and cytotoxic T cells (CTLs) within tumor tissues, ultimately reversing the ITM into an immune-responsive milieu. Furthermore, we found that the combination mild PTT with AuNR@SiO2 and anti-PD-L1 therapy could lead to the 100% complete regression of primary tumors and immunological memory to prevent tumor recurrence. Collectively, this study demonstrates that AuNR@SiO2 with a robust methodology capable of continuously inducing mild temperature accurately within the ITM holds promise as an approach to achieve the precision photothermal immunotherapy.

Carbon monoxide-based immunogenic cell death amplifier remodels the hypoxic microenvironment for tumor sono-immunotherapy

Ultrasound-activated tumor catalytic therapy has great potential in clinical cancer treatment. However, the hypoxic and immunosuppressive tumor microenvironment impairs the efficacy of solid tumor treatment, leading to a high recurrence rate of metastatic cancer. Thus, reversing the tumor microenvironment remains a formidable challenge. To circumvent these critical issues, we employ ultrasound-activable carbon monoxide (CO) gas therapy and reactive oxygen species (ROS) production to trigger immunogenic cell death (ICD) and alleviate tumor hypoxia, achieving a combination of tumor therapy and reversal of immunosuppression to overcome the limitations of monotherapy and control tumor metastasis and recurrence. In brief, we first use copper sulfide (CuS) nanosheet as a highly efficient ultrasound-controllable catalytic nanomaterial, which can catalyze carbon dioxide, water, and oxygen to produce CO, oxygen, and ROS. Moreover, as a Fenton-like catalyst, it can catalyze hydrogen peroxide at tumor sites to generate ROS. The generated CO can attack mitochondria to accelerate their metabolism and produce more ROS, thus inducing ICD. In addition, the generation of oxygen can not only serve as the source of ROS, but it can also relieve tumor hypoxia and normalize the tumor immunosuppressive microenvironment. This results in the maturation of dendritic cells and the enhancement of T-lymphocyte recruitment and infiltration, further stimulating the antitumor immune response, mediating the regression of primary and distal tumors, and inhibiting lung metastasis. This in situ sono-activable catalytic therapy strategy minimizes the toxicity of CO and ROS leakage and provides a novel approach for designing new ICD inducers and improving therapeutic effects.

Abstract A078: Intratumoral administration of ultra high-concentration Nitric Oxide (UNO) and anti-PD-1 treatment leads to high tumor regression rates and prolonged survival in tumor-bearing mice

Abstract Background: Immune checkpoint inhibitors have transformed clinical oncology. However, their use is limited to a subset of tumors as response is observed in only ~20% - 50% of patients. Nitric Oxide (NO) is a signaling molecule, found to have a key function in multiple diseases, including cancer. Furthermore, it has been shown to activate anti-tumor immune responses. Previously, we reported that treating CT26 tumor-bearing mice with ultra-high-concentration gaseous NO (UNO) followed by tumor resection stimulated antitumor immune responses. In a previous study, we showed that treatment of 50,000 ppm NO for 10 minutes in combination with anti-mouse-PD-1 (anti-mPD-1) resulted in primary and secondary tumor complete regression in 53% of treated mice at day 100 post-UNO treatment (1). Here, we investigated a higher dose NO over a shorter delivery time to evaluate the hypothesis of improved efficacy of a combination NO and programmed cell death protein-1 (PD-1) antibody in treating CT26 tumor-bearing mice. In this study, we tested the potential efficacy of 100,000 ppm NO administered for 5-minutes in combination with anti-mPD-1. Methods: At day zero, 0.5 X 106 CT26 cells were injected to the right flank of Balb/c male mice (n=8 per group) and at Day three, CT26 cells were injected to the contralateral flank. On Day twelve, tumors (average size 75-100 mm3) were treated intratumorally with UNO (100,000 ppm, 5 minutes, flow rate ~0.2 liter per minute). Day thirteen anti-mPD-1 injections (5mg/kg, q3d, x 5) commenced. Post-treatment tumor volume and survival were monitored thereafter. Results: Complete regression of the primary tumor occurred in 2/8 (25%) of mice treated with combination of 5-minute UNO and anti-mPD-1, 26 days post-treatment. This is compared to 1/8 (12.5%) of controls treated with anti-mPD-1 alone and 0/8 (0%) treated with UNO alone. In the nitrogen + anti-mPD-1 group primary tumor regression occurred in 1/8 mice (12.5%), showing no benefit over anti-mPD-1. Six of eight (~75%) of the mice in the UNO+anti-mPD-1 arm are distant tumor free, compared to 3/8 – 4/8 (37.5% - 50%) in all control arms, resulting in 25% tumor-free mice in the UNO+anti-mPD-1 arm. Survival was increased in the UNO/anti-mPD-1 combination arm compared to anti-mPD-1 alone, 26 days post-treatment. Conclusion: UNO in combination with PD-1 blockade resulted in an increase in the proportion of mice that demonstrate regression of primary tumors, an increase in the number of tumor-free mice, and prolonged survival. Here we present a second study showing similar results at day 26 using a shorter duration of UNO. The results imply that UNO sensitizes CT26 tumors to anti-mPD-1 therapy with improved outcomes compared to each therapy alone. 1. Confino H, Dirbas FM, Goldshtein M, Yarkoni S, Kalaora R, Hatan M, et al. Gaseous nitric oxide tumor ablation induces an anti-tumor abscopal effect. Cancer Cell Int. 2022;22(1):405. Citation Format: Yana Epshtein, Gavin Choy, Jedidiah M. Monson, Hila Confino, Frederick M. Dirbas, Selena Chaisson. Intratumoral administration of ultra high-concentration Nitric Oxide (UNO) and anti-PD-1 treatment leads to high tumor regression rates and prolonged survival in tumor-bearing mice [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A078.

462. MAJOR PATHOLOGIC RESPONSE IN ESOPHAGEAL ADENOCARCINOMA: SHOULD WE ADOPT A NEW PARADIGM IN DEFINING RESPONSE TO TREATMENTS?

Abstract Background Incidence of adenocarcinoma (ADC) of the esophagus is arising in Western countries and it is still burdened by a significant mortality. A complete primary tumor regression after neoadjuvant treatment is associated with improved long-term survival, however this favorable response is rarely achieved. The primary endpoint of this study was to determine whether the survival benefit associated with a complete tumor regression could be achieved also with a major, albeit subtotal, tumor response. Methods We evaluated all consecutive patients who underwent esophagectomy for cancer at 2 high-volume centers. Inclusion criteria were histologically confirmed ADC involving the thoracic esophagus or Siewert I and II cancers, treated by neoadjuvant chemotherapy (CT) or chemoradiotherapy (CRT) and surgery. Pathological tumor response was quantified using the Mandard score. Kaplan-Maier plots were used to estimate overall survival (OS) according to the TRG. Results Overall, 424 patients were recruited in the study period, 236 received CT and 188 CRT. The median follow-up time was 55 months. TRG 1 and 2 showed comparable OS curves both in the CT group (p = 0.76) and in the CRT group (p = 0.82) (Figure 1). TRG 1–2 were associated with a significantly improved OS compared to TRG 3–5 after CT (p = 0.004) and CRT (p = 0.0003). The trend was confirmed in the whole cohort, with TRG 1 and 2 patients showing comparable 5-years OS proportions (70% vs. 65%, p = 0.52) and a significantly improved survival compared to TRG 3–5 (p &amp;lt; 0.0001). Conclusion Tumor regression after neoadjuvant treatment is significantly associated with long term survival irrespective of the adopted regimen. The long-term survival was comparable between TRG 1 and TRG 2 patients after CT and CRT and in the overall population. This finding allowed us to define the criterion of major tumor response, which includes both TRG 1 and 2 patients, potentially creating a homogeneous and larger subgroup of subjects to be evaluated in future clinical trials.

Synergistic strategy based on mild phototherapy and deep tumor hypoxia reversal comprehensively remodels the tumor microenvironment for improved immunotherapy

Immunotherapy has shown remarkable therapeutic efficacy in triple-negative breast cancer (TNBC), but successful immune responses occur in only a subset of patients due to the hostile tumor microenvironment (TME). Specifically, low immunogenicity, dense extracellular matrix, and immunosuppressive environment in the TME are difficult to bypass for immunotherapy. The hypoxic environment of solid tumors not only contributes to an unfavorable TME but also functions in inhibiting the therapeutic effect of multiple antitumor methods, especially photodynamic therapy (PDT). In this study, we successfully developed a synergistic regulation nanosystem with albumin-mediated tumor targeted delivery of the photosensitizer IR780 and oxygen-generating nanoenzyme MnO2. As expected, MnO2 responsively catalyzed the decomposition of endogenous tumor H2O2 into O2, thereby enhancing the effect of PDT in triggering immunogenic cell death (ICD) and boosting tumor immunogenicity. Additionally, the enhanced PDT also functions in eliminating the tumor stromal barrier, facilitating the infiltration of effector T cells and therapeutics. The subsequent delivery of nanosystems containing MnO2 could reach deeper into the core of the tumor to alleviate severe hypoxia. Furthermore, relief of deep tumor hypoxia could significantly induce vascular normalization and reversal of tumor immunosuppression, decreasing the negative immunomodulatory cells such as Tregs and MDSCs. Resultantly, a positive feedback loop between mild phototherapy and deep hypoxia reversal was established using the synergistic strategy, which achieved comprehensive TME remodeling. Its combination with PD-L1 checkpoint blockades could lead to the regression of primary tumors and untreated metastasis tumors by inducing a strong systemic immune response, enhancing the immunotherapeutic efficacy for TNBC.

Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Radical Tumor Denervation Activates Potent Local and Global Cancer Treatment.

This preliminary study seeks to determine the effect of R&P denervation on tumor growth and survival in immunocompetent rats bearing an aggressive and metastatic breast solid tumor. A novel microsurgical approach was applied "in situ", aiming to induce R&P denervation through the division of every single nerve fiber connecting the host with the primary tumor via its complete detachment and re-attachment, by resecting and reconnecting its supplying artery and vein (anastomosis). This preparation, known as microsurgical graft or flap, is radically denervated by definition, but also effectively delays or even impedes the return of innervation for a significant period of time, thus creating a critical and therapeutic time window. Mammary adenocarcinoma cells (HH-16.cl4) were injected into immunocompetent Sprague Dawley adult rats. When the tumors reached a certain volume, the subjects entered the study. The primary tumor, including a substantial amount of peritumoral tissue, was surgically isolated on a dominant artery and vein, which was resected and reconnected using a surgical microscope (orthotopic tumor auto-transplantation). Intending to simulate metastasis, two or three tumors were simultaneously implanted and only one was treated, using the surgical technique described herein. Primary tumor regression was observed in all of the microsurgically treated subjects, associated with a potent systemic anticancer effect and prolonged survival. In stark contrast, the subjects received a close to identical surgical operation; however, with the intact neurovascular connection, they did not achieve the therapeutic result. Animals bearing multiple tumors and receiving the same treatment in only one tumor exhibited regression in both the "primary" and remote- untreated tumors at a clinically significant percentage, with regression occurring in more than half of the treated subjects. A novel therapeutic approach is presented, which induces the permanent regression of primary and, notably, remote tumors, as well as, evidently, the naturally occurring metastatic lesions, at a high rate. This strategy is aligned with the impetus that comes from the current translational research data, focusing on the abrogation of the neuro-tumoral interaction as an alternative treatment strategy. More data regarding the clinical significance of this are expected to come up from a pilot clinical trial that is ongoing.

Dynamic Profiling of the Immune Tumor Microenvironment in Locally Advanced Gastric Cancer Treated with Perioperative Chemotherapy

Introduction: In locally advanced gastric cancer (GC), FLOT represents the standard perioperative regimen and combination with immunotherapy is under investigation. However, the role of immune tumor microenvironment (TME) is poorly recognized in this setting. We aimed to study TME characteristics and dynamics during FLOT. Methods: Paired biopsy (PRE) and surgical (POST) samples of 25 patients treated with FLOT were prospectively analyzed. After collection of clinic-pathological data, NanoString analyses were performed. The primary objective of the study was to assess the changes induced by chemotherapy in POST compared to PRE samples. Results: The unsupervised hierarchical method analysis clearly distinguished PRE and POST samples, even though some cases showed high immune gene expression at baseline. When POST samples were compared with PRE, a differential expression in hyper-expressed gene sets related to cytotoxicity, T-cell functions, complement system, tumor necrosis factor superfamily, cell cycle, and regulation was recognized. Downstaging of the primary tumor (T-regression, measured by pathologic compared to clinical T stage) was the covariate most frequently associated with these changes. Using the immune cell profiling, cases with T-regression reported a significant increase of T, CD8+ T and B cells and a decrease in mast cells, while nonresponders demonstrated an increase of T, B, cytotoxic, and mast cells. Conclusion: Our analysis shows that FLOT significantly influences immune TME of GC. While relevant modifications preferentially occur in tumors showing primary tumor regression, response to treatment seems to be associated with a specific immune profile.

Tumor Microenvironment-Activatable Molecular Pro-theranostic Agent for Photodynamic and Immunotherapy of Cancer.

Cancer-associated fibroblasts (CAFs) are the major components of the tumor-associated matrix, and play an important role in tumor progression and immunosuppression. Therefore, precise theranostics of CAFs are beneficial to CAFs-targeted therapies. However, imaging agents enabling precise theranostics of CAFs have been rarely exploited. To tackle this issue, we develop a molecular pro-theranostic probe (FMP) with activatable fluorescence, photoacoustic (PA) imaging, and photodynamic therapy (PDT) in response to fibroblast activation protein α (FAPα) overexpressed in more than 90% types of CAFs and some tumor cells. Attributing to efficient activatable photo-toxicity towards CAFs and tumor cells together with activated immunogenic cell death (ICD), complete tumor regression of primary tumors and abscopal effect of distant tumors are observed on the 4T1 tumor-bearing mice model. By integration with PD-L1 checkpoint blockade immunotherapy, enhanced systemic immune responses have been evoked to obtain long-lasting tumor suppression of both primary and distant tumors as well as arrest systemic cancer metastasis in living mice. This article is protected by copyright. All rights reserved.

Intratumoral injection of oncolytic virus (H101) in combination with concurrent chemoradiotherapy for locally advanced cervical cancer

ObjectivesTo evaluate the efficacy of primary tumor bulk reduction and the safety of concurrent chemoradiotherapy in combination with H101, a type of oncolytic virus, for the treatment of locally advanced...

Comparison of the efficacy between immunochemotherapy and chemotherapy in gastric cancer accompanied with synchronous liver metastases: A real-world retrospective study.

Few studies have investigated the efficacy of comprehensive therapies, including immunotherapy, for gastric cancer with synchronous liver metastases (GCLM). We retrospectively compared the effect of immunochemotherapy and chemotherapy alone as conversion therapies on the oncological outcomes of patients with GCLM. The clinicopathological data of 100 patients with GCLM from February 2017 to October 2021 at our institution were retrospectively analyzed. Patients were divided into immunochemotherapy (n = 33) and chemotherapy-alone (n = 67) groups. Baseline clinicopathological data did not differ significantly between the two groups. The immunochemotherapy group had a higher overall response rate (59.4% vs. 44.0%, p = 0.029) and disease control rate (71.9% vs. 49.2%, p = 0.036) than the chemotherapy group. The immunochemotherapy group showed better tumor regression in the gastric mass, metastatic lymph nodes, and liver lesions than the chemotherapy group. Ten (30.3%) patients in the immunochemotherapy group and 13 (19.4%) patients in the chemotherapy group underwent surgery after conversion therapy. However, the difference was not statistically significant. The overall survival (OS) and progression-free survival (PFS) rates were better in the immunochemotherapy group than in the chemotherapy group. Treatment-related adverse events occurred in 24 (72.7%) and 47 (70.1%) patients in the immunochemotherapy and chemotherapy groups, respectively. As a conversion therapy for GCLM, immunotherapy yielded better primary and metastatic tumor regression and survival benefits, with no increase in adverse events compared to chemotherapy.