Outcome In Solid Tumors Research Articles

Systemic inflammatory markers in neoadjuvant pembrolizumab therapy for triple-negative breast cancer: Prognostic insights and nomogram construction.

e12649 Background: Systemic inflammatory markers derived from peripheral blood cells, such as the neutrophils and lymphocytes ratio (NLR), derived neutrophil lymphocyte ratio (dNLR), platelet-lymphocyte ratio (PLR), and lymphocyte–monocyte ratio (LMR), have shown promise as prognostic markers. Currently, neoadjuvant treatment (NACT) for early triple-negative breast cancer (eTNBC) involves the addition of an immune therapy, and little is known about the variation of these markers in this specific context. Methods: This study evaluated two groups who received NACT for eTNBC in a single third-level cancer center. The first received NACT with EC X4 and a weekly paclitaxel regimen, the second pembrolizumab and NACT. A total of 70 patients were included, 37 patients in the pembrolizumab group. NLR was defined as the absolute blood neutrophil count (N) divided by the absolute lymphocyte count (L), dNLR was defined as the N divided by the derived L (absolute leukocyte count — N), PLR was defined as the absolute platelet count divided by the L, LMR was defined as the L divided by the absolute monocyte count. Association between systemic inflammatory markers and pathological complete response (pCR) was analyzed using statistical tests. Inflammatory markers were evaluated at the time of diagnosis, at the time of chemotherapy regimen change, and 1 week before surgery. The χ2 test or Fisher’s exact test was used for correlation and Student’s t-test to compare different groups. Results: The pCR rates were 60,6% in the standard therapy and 77,8% in the pembrolizumab. There were no significant differences in clinical characteristics between the two groups. NLR, dNLR, PLR and LMR at 6 months showed significant differences compared to baseline levels. dNLR in the immunotherapy group, at the end of therapy, showed statistical significance with the Welch Two Sample t-test with p-value = 0.001. Variables were weighted with respect to the type of treatment and the outcome was assessed as pCR. On the basis of these data, a nomogram was constructed to predict the likelihood of achieving pCR in patients undergoing neoadjuvant pembrolizumab therapy. Conclusions: This study highlights the potential of systemic inflammatory markers as prognostic indicators in patients with eTNBC undergoing NACT. dNLR is a novel biomarker associated with clinical outcome in solid tumors. In this study, for the first time, a correlation was found between the use of pembrolizumab and the change in dNLR and consequently its impact on pCR. A nomogram was constructed to predict the outcome of pCR. [Table: see text]

Identification of Novel Tumor Pyroptosis-Related Antigens and Pyroptosis Subtypes for Developing mRNA Vaccines in Pancreatic Adenocarcinoma.

As one of the important components of immunotherapies, mRNA vaccines have displayed promising clinical outcomes in solid tumors. Nonetheless, their efficacy remains unclear in pancreatic adenocarcinoma (PAAD). Given the interaction of pyroptosis with anticancer immunity, our study aims to identify pyroptosis-related antigens for mRNA vaccine development and discern eligible candidates for vaccination. Utilizing gene expression data from TCGA and ICGC, we integrated RNA-seq data and compared genetic alterations through cBioPortal. Differential gene expressions were integrated using GEPIA. Relationships between immune cell abundance and tumor antigens were analyzed and visualized via TIMER. WGCNA facilitated the clustering of pyroptosis-related genes, identification of hub genes, and pathway enrichment analyses. Pyroptosis landscape was depicted through graph learning-based dimensional reduction. Four overexpressed and mutant pyroptosis-related genes associated with poor prognosis were identified as potential antigens for mRNA vaccines in PAAD, including ANO6, PAK2, CHMP2B, and RAB5A. These genes displayed positive associations with antigen-presenting cells. PAAD patients were stratified into three pyroptosis subtypes. Notably, the PS3 subtype, characterized by a lower mutation count and TMB, exhibited "cold" immunological traits and superior survival compared to other subtypes. The pyroptosis landscape exhibited considerable heterogeneity among individuals. Furthermore, the turquoise module emerged as an independent prognostic indicator and patients with high expressions of hub genes might not be suitable candidates for mRNA vaccination. In PAAD, ANO6, PAK2, CHMP2B, and RAB5A are prospective pyroptosis-related antigens for mRNA vaccine development, which holds potential benefits for patients classified as PS3 and those with diminished hub gene expressions, providing insights into personalized mRNA vaccine strategies.

Abstract 1495: Lipocalin-2 promotes breast cancer metastasis via tumor cell intrinsic and extrinsic mechanisms

Abstract While metastasis is the primary factor predicting poor outcomes in solid tumors, survival is lowest in patients initially diagnosed with a localized malignancy that then progresses to metastatic disease. Notably, nearly 25% of early-stage breast cancers (BCs) metastasize during treatment or following an initial positive response to therapeutic intervention. To define the molecular and cellular factors that contribute to metastatic progression of BC, we previously developed the Py230-C57Bl/6 syngeneic experimental metastasis model for interrogating mechanisms by which soluble factors condition premetastatic lung tissue to potentiate BC cell seeding/expansion. Using this model and the TCGA, we identified lipocalin-2 (Lcn2) as a molecular candidate that is upregulated in lung-tropic Py230 cells and other human triple-negative breast cancer (TNBC) cells, and that predicts poor outcomes in human BCs. While Lcn2 has been previously reported to mediate BC progression in genetically engineered mouse models, its mechanism(s) of action remain undefined. Here, we demonstrate that Py230 cell-secreted Lcn2 is necessary for optimal reprogramming of the premetastatic lung during metastatic progression. In agreement with these data, we defined a cell intrinsic role for Lcn2 in BC cell organoid assembly/invasion and expression of proinflammatory factors. To define BC cell extrinsic roles for Lcn2 in remodeling the premetastatic lung, we collected global transcriptome and single-cell spatial proteome data for lung tissue from C57Bl/6 mice systemically educated with mock media or media conditioned with Py8119 (Lcn2low) or Py230 (Lcn2hi) BC cells. Mice receiving Py230 conditioned media treatments were further divided between two groups – one receiving an isotype control IgG and the other receiving an Lcn2 immunoneutralizing antibody. Global transcriptome data was used to determine novel gene set enrichment signatures and clinically relevant interactomes – notable candidates predicted to cooperate with Lcn2 in decreasing patient survival were affiliated with cilia biogenesis and function. Single-cell spatial proteome data were analyzed for 28 different cell populations within the premetastatic lung. Interestingly, Py230 cell-derived Lcn2 did not affect the percentage of ciliated epithelial cells indicating that the global transcriptome data referenced above represent a real increase in expression of cilia-related genes and not an increase in cilia-positive cell types. Notably, we identified that Lcn2 increased the percentage of CD45neg/Despos mechanomodulatory cells and proliferating CD45pos/CD3pos/CD4neg/CD8pos cytotoxic T cells in the premetastatic lung. Taken together, these data define new targets around which new therapeutic strategies can be developed to improve BC patient outcomes. Citation Format: Joshua Gamez, Francesca Sanchez, Gabriela Ortiz-Soto, Jane Cox, Amir Gerami, Jonathan A. Kelber. Lipocalin-2 promotes breast cancer metastasis via tumor cell intrinsic and extrinsic mechanisms [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 1495.

Abstract 4012: SOT302: Dual expression of exogenous glutamine oxaloacetate transaminase (GOT2) and TP53-induced glycolysis and apoptosis regulator (TIGAR) enhance CAR T cell activity in preclinical solid tumor models

Abstract Background: Despite success in hematological malignancies, CAR T therapy has had limited efficacy against solid tumors. The suppressive tumor microenvironment limits CAR T activity through various mechanisms including competition for available nutrients and chronic stimulation resulting in reduced effector functions or T cell exhaustion. CAR T cells with enhanced metabolic fitness or more durable memory phenotype could potentially improve the clinical outcome in solid tumors. GOT2 plays an important role in mitochondrial function and maintenance of redox homeostasis. We have previously demonstrated enhancement of CAR T cells overexpressing GOT2. TIGAR is an enzyme known to promote antioxidative activites and reduce reactive oxygen species and has a role in protecting against apoptosis. Here we tested SOT302 CAR T cells expressing both GOT2 and TIGAR in preclinical solid tumor models. Results: Expression of GOT2 and TIGAR transgenes were confirmed by qRT-PCR and western blot. Activity of GOT2 and TIGAR were confirmed by measuring aminotransferase activity (AST) and glutathione production, respectively. Compared to control CAR T cells, SOT302 is enriched for CD8+ Tscm cells and has a higher percentage functional, non-senescent (CD28+CD57-) cells. SOT302 has similar cytokine expression and cytotoxicity in standard co-culture assays compared to controls. SOT302 cells were chronically stimulated with plate-bound antigen every 3-4 days for 4 rounds. SOT302 had greater expansion of cells and were less exhausted and had better cytolytic capacity compared to controls. SOT302 cells were then evaluated in tumor xenograft mouse models. Consistent with our previous findings, CAR T cells expressing the single GOT2 transgene were more efficacious compared to CAR T cells alone. Expression of the single TIGAR transgene had no apparent benefit over CAR alone, however SOT302 cells expressing both GOT2 and TIGAR had superior anti-tumor activity compared to CAR alone and CAR+GOT2. No overt toxicity or significant body weight loss was observed. Ex vivo analyses to measure peripheral expansion, tumor infiltration and exhaustion were also performed. Preliminary findings indicate that SOT302 has better peripheral expansion compared to CAR alone and similar expansion compared to CAR+GOT2 controls. SOT302 cells had better tumor infiltration compared to both the CAR alone and CAR+GOT2 cells. Tumor infiltrating SOT302 cells also exhibited lower levels of exhaustion compared to CAR alone or CAR+GOT2 controls. Summary: SOT302 cells express exogenous GOT2 and TIGAR transgenes and have superior anti-tumor activity in preclinical solid tumor models. These data suggest that SOT302 may be a promising candidate for patients with solid tumor cancers. Citation Format: Emily Kuiper, Samyabrata Bhaduri, Daniel Garafola, Kshitij Sharma, Jennifer Coccia, Kathleen Whiteman, Amy Jensen-Smith. SOT302: Dual expression of exogenous glutamine oxaloacetate transaminase (GOT2) and TP53-induced glycolysis and apoptosis regulator (TIGAR) enhance CAR T cell activity in preclinical solid tumor models [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 4012.

Abstract 2620: BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity

Abstract 5T4 is a highly expressed tumor-associated antigen associated with adverse clinical outcomes in solid tumors, and is an attractive therapeutic target due to low expression on normal adult tissues. While several therapeutic agents targeting 5T4 antigen are currently being evaluated in human clinical trials, none have yet entered the market. Another target, MUC1, is currently under clinical investigation, with most drugs in clinical trials showing limited efficacy due to shedding of the target antigen MUC1-N. 5T4 and MUC1 are commonly co-expressed in various solid tumors, including lung, breast, colorectal and pancreatic cancers, suggesting that targeting both antigens with a single drug could be a promising therapeutic strategy. We previously identified and evaluated antibodies targeting human 5T4 and MUC1-C (cleaved MUC1) using RenLite® fully human common light chain mice. Here, selected antibodies were constructed into 5T4 × MUC1 bispecific antibodies (bsAb). The 5T4-MUC1 bsAb demonstrated high avidity in multiple human tumor cell lines by flow cytometry. Notably, the parental 5T4 antibody also binds strongly to many tumor cell lines. Internalization assays demonstrate that the internalization of 5T4-MUC1 bsAb in breast cancer cells was enhanced compared to the parental anti-5T4 and anti-MUC1 monoclonal antibodies, as measured by Incucyte® live cell imaging. Subsequently, the 5T4-MUC1 bsAb was then conjugated with monomethyl auristatin E (MMAE) to generate 5T4 x MUC1 bsADC (BCG016). Cytotoxicity assays indicate that BCG016 improved tumor cell killing in vitro compared to benchmark ADCs, and in vivo efficacy studies showed superior anti-tumor efficacy of BCG016 in patient-derived NSCLC xenografts compared to benchmark ADCs and parental ADC combination therapy. In summary, we have generated a novel bispecific ADC targeting 5T4 and the cleaved MUC1-C protein, which remains membrane-bound on tumor cells. The 5T4-MUC1 bsADC showed superior anti-tumor efficacy in PDX models and has the potential to be a novel therapeutic for 5T4 and MUC1 co-expressing tumors. Citation Format: Zhenyan Han, Chengzhang Shang, Yifu Zhang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity [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 2620.

Targeting KRAS and SHP2 signaling pathways for immunomodulation and improving treatment outcomes in solid tumors.

Historically, KRAS has been considered 'undruggable' inspite of being one of the most frequently altered oncogenic proteins in solid tumors, primarily due to the paucity of pharmacologically 'druggable' pockets within the mutant isoforms. However, pioneering developments in drug design capable of targeting the mutant KRAS isoforms especially KRASG12C-mutant cancers, have opened the doors for emergence of combination therapies comprising of a plethora of inhibitors targeting different signaling pathways. SHP2 signaling pathway, primarily known for activation of intracellular signaling pathways such as KRAS has come up as a potential target for such combination therapies as it emerged to be the signaling protein connecting KRAS and the immune signaling pathways and providing the link for understanding the overlapping regions of RAS/ERK/MAPK signaling cascade. Thus, SHP2 inhibitors having potent tumoricidal activity as well as role in immunomodulation have generated keen interest in researchers to explore its potential as combination therapy in KRAS mutant solid tumors. However, the excitement with these combination therapies need to overcome challenges thrown up by drug resistance and enhanced toxicity. In this review, we will discuss KRAS and SHP2 signaling pathways and their roles in immunomodulation and regulation of tumor microenvironment and also analyze the positive effects and drawbacks of the different combination therapies targeted at these signaling pathways along with their present and future potential to treat solid tumors.

Comprehensive Analysis of Structural and Social Determinants of Health Leading to Delays in Seeking Hematologic Care: Survey of an Underserved Population with Hematologic Malignancies

Background: Disparities in outcomes based on age, race, and socioeconomic status are well-established among patients with hematologic malignancies. Timely access to health care is essential for successful treatment of aggressive hematologic malignancies. Delays in receiving treatment have been linked to worse cancer outcomes in solid tumors and is presumed to lead to worse outcomes in hematologic malignancies. Memphis, owing to its geography, draws patients from Tennessee, Arkansas, and Mississippi for complex medical care. Patients at our institution frequently belong to underserved communities, including rural, impoverished, underinsured, and racial minority populations. In this exploratory study, we sought to characterize the potential structural and social barriers that patients in an underserved population with hematologic malignancies may face accessing oncologic care around the time of their cancer diagnosis. Methods: A cross-sectional survey was conducted to better understand potential barriers to accessing hematologic care in the greater Memphis area. The survey was developed through a review of existing literature on this topic (i.e., Anderson's conceptual model for healthcare utilization), as well as from the investigators' clinical experience treating cancer patients. Several components of social determinants of health (SDOH), including psychosocial, economic, health literacy, behavioral, health care perceptions, cultural, structural, environmental, clinical, and chronic stress domains, were queried in this 56-item survey. Most items were presented as closed-ended statements on a Likert scale. Response categories for analyses were collapsed into two levels (eg, “agree” for “somewhat” or “strongly”; “concerned” for “somewhat” or “very”). Descriptive statistics, including percentages, means, medians, and ranges, were used to characterize the sample. Results: A total of 41 out of 46 consented patients completed the survey (response rate: 89.1%). The median age of respondents was 56.3 years (Table 1). Most had lymphoma (48.8%), followed by acute myeloid leukemia (17.1%) and multiple myeloma (12.2%). The majority of respondents were male (53.7%) and Black or African American (46.3%). Over half of the sample reported an annual income of less than $25,000 (57.1%) and nearly a third were uninsured at the time of their cancer diagnosis (32.5%). Approximately 44% of respondents believed that medical attention to their cancer symptoms was delayed prior to their cancer diagnosis by a doctor. Of this subset, the majority attributed the delay to economic factors (64%), followed by health literacy (58%), structural (51%), healthcare perceptions (47%), behavioral (45%), psychosocial (45%), chronic stress (43%), cultural (15%) and clinical (11%) reasons (Table 2). Conclusions and Implications: To our knowledge, this is the first survey study to investigate the factors from a patient's perspective that contributed to delays in seeking care for hematologic malignancies. This pilot study establishes the feasibility of approaching an extremely underserved population about sharing their experiences accessing medical care around the time of their cancer diagnosis as well as participating in research. Along with already well-established economic, health literacy, psychosocial, and structural barriers, respondents endorsed that health care perceptions and chronic stress contributed almost equally to delays in seeking care. Cultural and clinical barriers contributed the least. Our study findings are limited by a skewed patient selection toward those who survived initial hospitalization and treatment and is not inclusive of the sickest patients in our patient population who experienced neglected cancer symptoms. A mixed-methods, focus-group based study is planned as the next step to substantiate these findings and allow us to gain a deeper understanding into the social disparities that most heavily impact this underserved population. Acknowledgement of Funding: This research was supported by the American Society of Hematology through the ASH HONORS Award.

Prognostic value of human leukocyte antigen G (HLA-G) expression in solid tumors: A systematic review and meta-analysis.

e14639 Background: Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression. Methods: We performed a systematic review and meta-analysis on the role of HLA-G expression and outcome in solid tumors. A total of 25 studies met the inclusion criteria comprising data from 4871 patients reporting overall survival (OS) outcomes, and 961 patients, in 5 studies, for disease free survival (DFS). This study was performed in accordance with PRISMA guidelines and registered in PROSPERO. Results: HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance. Conclusions: We describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors.

Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis.

Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression. In this article we performed a systematic review and meta-analysis on the association between HLA-G expression and outcome in solid tumors. This study was performed in accordance with PRISMA guidelines and registered in PROSPERO. A total of 25 studies met the inclusion criteria. These studies comprised data from 4871 patients reporting overall survival (OS), and 961 patients, reporting disease free survival (DFS). HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance. In summary, we describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022311973.

Abstract LB213: Identification of DM004, a first-in-class anti-5T4/MET bispecific antibody-drug conjugate

Abstract Aberrant MET signaling is frequently found in various types of solid tumors, and is correlated with oncogenic transformation, treatment resistance and poor prognosis. While MET remains an attractive therapeutic target, it is widely expressed on the surface of epithelial and endothelial cells, including normal tissues and tumors. To date, MET-targeting agents are associated with adverse clinical effects, including hypoalbuminemia, peripheral edema and pneumonitis, indicating that alternate treatments and/or modalities are needed. Intriguingly, MET antigen is commonly co-expressed with the oncofetal antigen 5T4 in various cancer types, including head and neck, lung and pancreatic cancer. While 5T4 is highly expressed on primary and metastatic cancers and is associated with adverse clinical outcomes in solid tumors, expression on normal adult tissues is very limited. Although several therapeutic agents targeting 5T4 antigen are currently being evaluated in human clinical studies, none have yet entered the market. To address these challenges, we hypothesized that targeting both MET and 5T4 with a bispecific antibody-drug conjugate (BsADC) could provide a more targeted therapeutic strategy to effectively eliminate tumor cells and reduce systemic toxicity. Here, we report that we have successfully generated two bispecific antibody candidates targeting both 5T4 and MET. The candidates were conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker to generate DM004 BsADCs, i.e., Top1-MMAE and Top2-MMAE. In vitro, DM004 BsAbs demonstrated enhanced internalization in the NCI-H226 cell line compared to its parental monoclonal and monovalent anti-5T4 and anti-MET antibodies. In vivo, DM004 BsADCs exhibited robust anti-tumor activity in cell line-derived and patient-derived xenografts of gastric cancer and lung cancer, respectively. In particular, DM004 Top2-MMAE outperformed benchmark ADCs in lung BP0508 PDX models. In summary, we have identified a novel BsADC which may be a promising future treatment for cancers co-expressing 5T4 and MET. Citation Format: Zhenyan Han, Chengzhang Shang, Wenjuan Dai, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. Identification of DM004, a first-in-class anti-5T4/MET bispecific antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB213.

Abstract 3230: Tumor microenvironment modulation by immunotherapy sensitizes solid tumors to radiation

Abstract Radiation therapy (RT) has been prevalently implemented to treat cancer in clinical settings by inducing DNA damage in tumor cells. However, tumor microenvironmental factors such as severe hypoxic conditions and vascular anomalies attenuate the therapeutic efficacy of RT, thus resulting in unsatisfactory outcomes in solid tumors. Recently, Immune checkpoint blockade (ICB) has improved immune recognition to tumor cells and normalized tumor vasculature to diminish hypoxia in solid tumors. Herein, we suggest that RT combined with ICB synergistically alters tumor microenvironments, thus facilitating the recruitment of cytotoxic immune cells into tumors as well as sensitizing radiation effectiveness. RT in combination with ICB not only normalized tumor vasculature to reduce hypoxia, but also increased anti-tumor effects from immune-mediated toxicity and DNA damage-mediated apoptosis in several solid tumor-bearing mouse models to a greater extent than did either monotreatment of RT or ICB. This study will provide mechanistic insight into synergistic effects conferred by RT and ICB as well as a strong preclinical rationale for combining the two therapeutic modalities in human cancers. Citation Format: Minjeong Kang, DaeYong Lee, Yifan Wang, Betty Kim, Wen Jiang. Tumor microenvironment modulation by immunotherapy sensitizes solid tumors to radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3230.

Changes in circulating tumor DNA and outcomes in solid tumors treated with immune checkpoint inhibitors: a systematic review

BackgroundQuantification of circulating tumor DNA (ctDNA) levels is a reliable prognostic tool in several malignancies. Dynamic changes in ctDNA levels in response to treatment may also provide prognostic information. Here,...

Hemoglobin, albumin, lymphocyte, and platelet (HALP) score and cancer prognosis: A systematic review and meta-analysis of 13,110 patients.

We sought to explore the prognostic role of the hemoglobin, albumin, lymphocyte, and platelet (HALP) score on survival outcomes in patients with solid tumors by performing a systematic review and meta-analysis. PubMed, EMBASE and Web of Science were searched for relevant articles through 02 Nov 2022. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were extracted and pooled to assess the association of the HALP score with survival outcomes in solid tumors using Stata 15.0. The primary outcome was overall survival (OS), and the secondary outcomes were cancer-specific survival (CSS) and progression/disease/recurrence-free survival (PFS/DFS/RFS). A total of 28 studies (31 cohorts) comprising 13,038 patients were enrolled. A low HALP score was associated with decreased OS (HR, 1.61; 95% CI, 1.44-1.81; P<0.001), CSS (HR, 1.80; 95% CI: 1.54-2.09; P<0.001) and PFS/DFS/RFS (HR, 1.61; 95% CI: 1.45-1.80; P<0.001). The prognostic value of HALP on OS was observed across various tumor types and tumor stages. meta-regression found that tumor stage was the major source of the heterogeneity for OS. A low pretreatment HALP score is a reliable and negative prognostic biomarker for survival outcomes in patients with cancer.

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors

Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies. Co-alteration landscapes were largely similar across KRAS mutations but distinct from KRAS wild-type, though differences were observed in some tumor types for tumor mutational burden, PD-L1 expression, microsatellite instability, and other mutational signatures. Prognosis of KRAS-mutant versus other genomic cohorts of lung, pancreatic, and colorectal cancer were assessed using a real-world clinicogenomic database. As specific KRAS inhibitors and combination therapeutic strategies are being developed, genomic profiling to understand co-alterations and other biomarkers that may modulate response to targeted or immunotherapies will be imperative.

Quantitative spatial evaluation of tumor-immune interactions in the immunotherapy setting of metastatic melanoma lymph nodes.

Immune cell infiltration into the tumor microenvironment is generally associated with favorable clinical outcomes in solid tumors. However, the dynamic interplay among distinct immune cell subsets within the tumor-immune microenvironment as it relates to clinical responses to immunotherapy remains unresolved. In this study, we applied multiplex immunofluorescence (MxIF) to spatially characterize tumor-immune interactions within the metastatic melanoma lymph node. Pretreatment, whole lymph node biopsies were evaluated from 25 patients with regionally metastatic melanoma who underwent subsequent anti-PD1 therapy. Cyclic MxIF was applied to quantitatively and spatially assess expression of 45 pathologist-validated antibodies on a single tissue section. Pixel-based single cell segmentation and a supervised classifier approach resolved 10 distinct tumor, stromal and immune cell phenotypes and functional expression of PD1. Single cell analysis across 416 pathologist-annotated tumor core regions of interest yielded 5.5 million cells for spatial evaluation. Cellular composition of tumor and immune cell subsets did not differ in the tumor core with regards to recurrence outcomes (p>0.05) however spatial patterns significantly differed in regional and paracrine neighborhood evaluations. Specifically, a regional community cluster comprised of primarily tumor and dendritic cells was enriched in patients that did not experience recurrence (p=0.009). By an independent spatial approach, cell-centric neighborhood analyses identified an enrichment for dendritic cells in cytotoxic T cell (CTL) and tumor cell-centric neighborhoods in the no recurrence patient response group (p<0.0001). Further evaluation of these neighborhoods identified an enrichment for CTL-dendritic cell interactions in patients that did not experience recurrence (p<0.0001) whereas CTL-macrophage interactions were more prevalent in CTL-centric neighborhoods of patients who experienced recurrence (p<0.0001). Overall, this study offers a more comprehensive evaluation of immune infiltrates and spatial-immune signatures in the metastatic tumor-immune microenvironment as it informs recurrence risk following immunotherapy.

Nanoparticle-Based Drug Delivery Systems Targeting Tumor Microenvironment for Cancer Immunotherapy Resistance: Current Advances and Applications.

Cancer immunotherapy has shown impressive anti-tumor activity in patients with advanced and early-stage malignant tumors, thus improving long-term survival. However, current cancer immunotherapy is limited by barriers such as low tumor specificity, poor response rate, and systemic toxicities, which result in the development of primary, adaptive, or acquired resistance. Immunotherapy resistance has complex mechanisms that depend on the interaction between tumor cells and the tumor microenvironment (TME). Therefore, targeting TME has recently received attention as a feasibility strategy for re-sensitizing resistant neoplastic niches to existing cancer immunotherapy. With the development of nanotechnology, nanoplatforms possess outstanding features, including high loading capacity, tunable porosity, and specific targeting to the desired locus. Therefore, nanoplatforms can significantly improve the effectiveness of immunotherapy while reducing its toxic and side effects on non-target cells that receive intense attention in cancer immunotherapy. This review explores the mechanisms of tumor microenvironment reprogramming in immunotherapy resistance, including TAMs, CAFs, vasculature, and hypoxia. We also examined whether the application of nano-drugs combined with current regimens is improving immunotherapy clinical outcomes in solid tumors.

Novel treatment approaches for HER2 positive solid tumors (excluding breast cancer).

Human epidermal growth factor 2 (HER2) alterations (protein overexpression, gene amplification and mutation) play a key role in oncogenesis and are more likely correlated to poorer outcome in solid tumors. We reviewed recently published studies in the last 18 months on novel treatment approaches for HER2 positive solid tumors (excluding breast cancer). Results of clinical studies assessing anti-HER2 therapies have been recently issued.One of the most promising drugs is transtuzumab deruxtecan, an antibody-drug conjugate which demonstrated clinically meaningful activity in gastric or gastroesophageal junction cancer and colorectal cancers.Small molecules such as poziotinib, pyrotinib, neratinib, which target both epidermal growth factor receptor (EGFR) and HER2 also showed promising activity, especially in heavily pretreated ERRB2-mutated non-small cell lung cancer (NSCLC) cancer patients. Yet, these findings need to be confirmed in confirmatory randomized trials with larger cohorts.Trastuzumab-based combinations with chemotherapy or immune checkpoint inhibitors are under development with promising results, but not in all HER2 tumors. Emerging adverse events with anti-HER2 are interstitial pneumopathy and diarrhea. Tyrosine kinase inhibitors, antibody drug conjugate in monotherapy and combinations are emerging strategies in many HER2-positive cancers; HER2 therapies are now part of standard of care of HER2-amplified gastric or gastroesophageal junction cancer. Data are pending on several unmet medical needs.

Production and characterization of virus-free, CRISPR-CAR T cells capable of inducing solid tumor regression

BackgroundChimeric antigen receptor (CAR) T cells have demonstrated high clinical response rates against hematological malignancies (e.g., CD19+ cancers) but have shown limited activity in patients with solid tumors. Recent work...

KIR2DS2 Expression Identifies NK Cells With Enhanced Anticancer Activity.

NK cells are promising cellular therapeutics against hematological and solid malignancies. Immunogenetic studies have identified that various activating killer cell Ig-like receptors (KIRs) are associated with cancer outcomes. Specifically, KIR2DS2 has been associated with reduced incidence of relapse following transplant in hematological malignancies and improved outcomes in solid tumors, but the mechanism remains obscure. Therefore, we investigated how KIR2DS2 expression impacts NK cell function. Using a novel flow cytometry panel, we show that human NK cells with high KIR2DS2 expression have enhanced spontaneous activation against malignant B cell lines, liver cancer cell lines, and primary chronic lymphocytic leukemia cells. Surface expression of CD16 was increased on KIR2DS2high NK cells, and, accordingly, KIR2DS2high NK cells had increased activation against lymphoma cells coated with the clinically relevant anti-CD20 Abs rituximab and obinutuzumab. Bulk RNA sequencing revealed that KIR2DS2high NK cells have upregulation of NK-mediated cytotoxicity, translation, and FCGR gene pathways. We developed a novel single-cell RNA-sequencing technique to identify KIR2DS2+ NK cells, and this confirmed that KIR2DS2 is associated with enhanced NK cell-mediated cytotoxicity. This study provides evidence that KIR2DS2 marks a population of NK cells primed for anticancer activity and indicates that KIR2DS2 is an attractive target for NK-based therapeutic strategies.

Changes in circulating tumor DNA (ctDNA) and outcomes in solid tumors treated with immune checkpoint inhibitors (ICIs).

2544 Background: Quantification of ctDNA levels can be a reliable prognostic tool in several malignancies. More recently, detection of genomic alterations in ctDNA have been validated as a predictive biomarker to guide treatment planning. Dynamic changes in ctDNA levels over time and in response to treatment may also provide prognostic information. However, less is known about the value of changes to ctDNA levels in response to immune checkpoint inhibitors (ICIs). Methods: We searched MEDLINE (host:PubMed) and reviewed trials exploring outcomes of patients with advanced solid tumors receiving ICIs in which outcomes were reported based on changes to ctDNA levels. ctDNA clearance was defined as reported in individual trials. Typically, this was defined as either &gt;50% reduction or a reduction to undetectable levels. We extracted progression free survival (PFS) and/or overall survival (OS) values, related 95% Confidence intervals (CI) and/or p-values. Data were then included in a meta-analysis utilizing the generic inverse variance and random effects model. Variation in effect size was examined using random effects meta-regression analysis. Results: A total of 17 trials were included in the meta-analysis; ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. Method of detection included next generation sequencing and/or droplet digital polymerase chain reaction assays. Overall, low to undetectable ctDNA levels, measured 6-16 weeks after starting treatment was associated with significantly better PFS, (HR 0.20 95% CI, 0.14-0.28; p&lt;0.001). Similarly, OS was superior in patients with substantially reduced or undetectable ctDNA levels after receiving ICIs, (HR 0.18, 95% CI, 0.12-0.26; p&lt;0.001. The results were consistent across all disease sites, lines of treatment, level of change (undetectable vs. &gt;50% reduction) and whether treatment exposure comprised single or multiple ICIs (see Table). Conclusions: In unselected advanced solid tumors, a substantial fall in ctDNA levels in response to ICIs is associated with substantial improvements in both PFS and OS. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs, or support treatment de-escalation strategies. Further research is needed to quantify variations in sensitivity between the available NGS assays, as well as differences discovery range between assay platforms. [Table: see text]