Antitumor Immunity In Patients Research Articles

Intratumoral Fc-optimized agonistic CD40 antibody induces tumor rejection and systemic antitumor immunity in patients with metastatic cancer.

While CD40 agonism is an attractive approach for activating antigen-presenting cells and initiating antitumor responses, previous attempts have encountered limited clinical efficacy coupled with toxicity. We previously demonstrated that interactions between the antibody Fc domain and the inhibitory receptor FcγRIIB are critical for enhanced antitumor activity. Here, we present the results of a phase 1 study on intratumoral administration of an anti-CD40 agonistic antibody (2141-V11) Fc-engineered to enhance FcγRIIB binding. Primary endpoints included safety, maximum tolerated dose (MTD), and recommended phase 2 dose. Secondary objectives included preliminary clinical activity and correlative studies from biospecimens. 2141-V11 was well-tolerated without dose-limiting toxicities and MTD was not reached. In ten evaluable patients with metastatic cancer, the overall response rate was 20%, with complete responses in two patients (melanoma and breast carcinoma) and stable disease in six patients. 2141-V11 induced tumor regression in injected and non-injected lesions, with increased leukocyte infiltration and tertiary lymphoid structures (TLS) formation in post-treatment biopsies. In a humanized mouse model for CD40 and FcγRs, 2141-V11 induced TLS formation in mice bearing orthotopic breast carcinoma, correlating with local and abscopal antitumor effects, systemic immune activation, and immune memory. These findings support the safety and efficacy of 2141-V11, warranting phase 2 studies and suggesting a unique mechanism of action for this Fc-enhanced immunotherapy (NCT04059588).

Options for enhancing specific antitumor immunity in patients with melanoma.

e21547 Background: The special interest in oncology is the research of the immune status of patients. Quantification of T-cell receptor excision rings (TREC) and B-cell receptor κ deletion elements (KREC) allows to evaluate a humoral and a cellular immunity. In melanoma, the effectiveness of the use of drugs to control immune points depends on the formation of specific antitumor immunity. Quantitative indicators of excision recombination rings reflect the formation of a different repertoire of T-cell receptors, which are an integral component in the formation of specific immunity. The understanding of changes in TREC levels in patients with melanoma during therapy with various drugs can improve the selection of patients for immunotherapy. The purpose of this study is to assess the dynamics of changes in quantitative indicators of the T-cell receptor during adjuvant therapy for melanoma. Methods: The study included 82 patients with melanoma. Among patients with melanoma, the proportion of male patients was 36.5% (30/82), female - 63.5% (52/82). The median age in the group of patients with cancer was 63 years [Q1-Q3: 52.8-75]. Results: From the results obtained, it follows that in cancer patients, a decrease in the number of TREC in the blood indicates the presence of immunodeficiency. The data obtained indicate significant changes in TREC in melanoma. Targeted therapy (dabrafenib + trametinib) and interferon therapy are accompanied by a significantly significant increase in the level of TREC, which indicates an increase in the formation of specific antitumor immunity. Conclusions: The results obtained demonstrate a significant decrease in TREC content in patients with melanoma compared to healthy individuals. Determination of TREC levels during adjuvant therapy demonstrated the effectiveness of dabrafenib in combination with trametinib and interferon α-2β, which is reflected in a significant increase in the T-cell receptor repertoire. The presented data indicate the possibility of using the method for determining the TREC level to predict the risk of cancer progression and the effectiveness of prescribed therapy.

LASSO regression and WGCNA-based telomerase-associated lncRNA signaling predicts clear cell renal cell carcinoma prognosis and immunotherapy response.

To investigate whether telomerase-associated lncRNA expression affects the prognosis and anti-tumor immunity of patients with renal clear cell carcinoma (ccRCC). A series of analyses were performed to establish a prognostic risk model and validate its accuracy. Immune-related analyses were performed to assess further the association between immune status, tumor microenvironment, and prognostic risk models. Eight telomerase-associated lncRNAs associated with prognosis were identified and applied to establish a prognostic risk model. Overall survival was higher in the low-risk group. The established prognostic risk model has a good predictive ability for the prognosis of ccRCC patients and provides a new possible therapeutic target for ccRCC.

Abstract 2652: NDI-101150 is a potent and highly selective HPK1 inhibitor that both synergizes with and differentiates from anti-PD1 immune checkpoint blockade

Abstract Introduction HPK1 is a member of the MAP4K family of protein serine/threonine kinases that negatively regulates activation signals in multiple immune cells and is an attractive therapeutic target for many cancers. Using structure-based drug design, we developed a highly selective HPK1 inhibitor, NDI-101150, with nanomolar potency and physiochemical properties suitable for once daily oral administration. Methods & Results HPK1 inhibition with NDI-101150 has a differentiated pharmacology profile when compared directly to PD1 blockade. NDI-101150 was able to overcome the immunosuppressive effects of prostaglandin E2, adenosine, and TGF-β on human T cell activation. HPK1 inhibition also directly limited the suppressive capacity of T regulatory cells. In contrast, anti-PD1 treatment was not able to overcome the immunosuppressive activity associated with any of these mechanisms. In vivo, HPK1 inhibition significantly enhanced the production of antigen-specific antibodies in response to immunization with both T-dependent and T-independent antigens, while anti-PD1 treatment had minimal to no effects on antibody production. In the EMT-6 syngeneic model, 7/10 mice receiving NDI-101150 exhibited complete tumor regressions, compared to only 1/10 from an anti-PD1 cohort. Furthermore, NDI-101150 established a robust and durable immune memory response as 100% of treated mice showed complete rejection of tumor growth upon subsequent re-challenge. HPK1 inhibition with NDI-101150 also shows robust synergy with PD1 blockade in vitro and in vivo. Both NDI-101150 and anti-PD1 were able to reinvigorate exhausted human T cells, restoring cytokine production and proliferative effects in mixed lymphocyte reactions. Further, in combination HPK1 inhibition and PD1 blockade synergized to enhance the activity of exhausted human T cells to an extent exceeding that observed with naïve human T cells in similar experiments. In vivo, while NDI-101150 or anti-PD1 treatments alone induced tumor growth inhibition in the murine CT-26 syngeneic tumor model, NDI-101150 and anti-PD1 in combination mediated complete tumor regressions in several mice. Furthermore, NDI-101150 seemed to induce a durable immune memory response as evidenced by the combination-treated animals showing complete rejection of tumor growth upon subsequent re-challenge, without any further dosing of NDI-101150. Conclusions Pharmacological inhibition of HPK1 with NDI-101150 represents a powerful system-wide immunomodulatory approach with the potential to enhance anti-tumor immunity in patients failing to respond to currently approved immune checkpoint therapies or in combination with immune checkpoint blockade therapies. NDI-101150 is currently being tested in a Phase 1/2 trial (NCT05128487) in patients with advanced solid tumors. Citation Format: David Ciccone, Fu-Shan Kuo, Scott Daigle, Neelu Kaila, Gene Yau, Mark Carlson, Denise Levasseur, Bhaskar Srivastava, Frank G. Basile, Christine Loh. NDI-101150 is a potent and highly selective HPK1 inhibitor that both synergizes with and differentiates from anti-PD1 immune checkpoint blockade [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 2652.

Microwave ablation enhances the systemic immune response in patients with lung cancer.

Microwave ablation (MWA) is a key alternative therapy to conventional surgery for the treatment of lung cancer. In addition to eliminating local tumors, MWA may promote antitumor immunological responses, such as abscopal effects in distant lesions. However, the intensity of MWA is limited and the underlying mechanisms are not well-defined. The present study assessed the impact of MWA on immune cell subsets and cytokines in patients with lung cancer. A total of 45 patients with lung cancer who underwent percutaneous lung tumor MWA were enrolled. Peripheral blood samples were collected before and 24 h after MWA and changes in immune cell subsets [lymphocytes, CD3+, CD4+ and CD8+ T cells, B cells and natural killer (NK) cells] and serum cytokine levels (IL-1β, IL-2, IL-4-6, IL-8, IL-10, IL-12p70, IL-17A and F, IL-22, TNF-α, TNF-β and IFN-γ) were assessed by flow cytometry and ELISA. The number of total lymphocytes, CD4+ T and NK cells in the peripheral blood significantly decreased 24 h after MWA, while number of CD8+ T cells remained stable, leading to a higher proportion of CD8+ T cells. In addition, the serum levels of IL-2, IL-1β, IL-6, IL-12p70, IL-22, TNF-α and IFN-γ were significantly increased 24 h after MWA, indicating a T helper 1 type immune response. The immune response in patients with advanced stage disease was comparable with patients in the early stage group; however, the number of total lymphocytes and CD3+ T cells significantly decreased and the ratio of CD4/CD8 and IL-2 levels significantly increased. The early immune response after MWA may contribute to systemic antitumor immunity in patients with both early and advanced disease. Thus, MWA may exhibit potential as a local therapy and trigger abscopal effects in distant lesions in patients with lung cancer.

On the Individualized Cancer Management

Individualized cancer management is the opposite of the standardized care adapted for current clinical practice by the mainstream medicine. It is not a fancy concept but a logic and inevitable reality derived from the intrinsic characteristics of cancer and host antitumor response. The question is not whether it should be done but how it is done. Previous efforts have identified various cancer driver gene mutations in individual cancer patient, which have provided basis for treating different patients with different drugs that target various mutated kinases that drive tumor replication. This progress has made one step towards individualized cancer management with limited success in the past two decades in certain type of cancer. A much larger step awaits to be made towards true individualized management of cancer. This step is based on the individual differences in antitumor immunity in different cancer patients. Because antitumor immunity is the most impacting factor for cancer survival once the malignancy of a tumor is established, to fully recognize and utilize this force in the battle against cancer maximize patient survival to the theoretical limit. A true individualized cancer therapy is not only based on personal situation for each patient, but must also satisfy the criterion that the outcome of selected therapy is predictable for that patient, a feature that current standardized care does not have. Thus, treating each patient according to the status of his antitumor immunity should be the most critical skills a physician needs to master when facing each individual cancer patient. In the past nine years, we have been exploring individualized management of cancer through recognizing and manipulating antitumor immunity in each patient. Our combined experiences indicate a significant benefit to patient survival with reduced costs even when such effort was not perfect in the past. With time and more learning, we see this practice becoming more and more practical in a clinical setting. When this individualized approach becomes guideline for cancer management, we will see a significant leap of clinical improvement on both patient survival and cancer cure rate.

γδT cells in patients with tumors of the nasal cavity and paranasal sinuses

The immunological factors can play an important role as predictive and prognostic biomarkers in oncopathology. Recently, non-conventional innate-like γδT-lymphocytes have received a lot of attention as a promising effector cell population for cancer immunotherapy. This study describes structural and functional subpopulations of γδT lymphocytes involved in antitumor immunity in patients with malignant and benign tumors of the nasal cavity and paranasal sinuses. The aim of the study was to estimate γδT cell subsets composition and functions in patients with neoplasms of nasal cavity and paranasal sinuses in order to characterize cellular immunity in tumor-associated pathological process.The peripheral venous blood was obtained from 21 patients (13 men and 8 women, average age of 63.0 (56.0-69.0) y. o.) with neoplasms of nasal cavity and paranasal sinuses, and 10 healthy donors. Lymphoid cells phenotype and production of intracellular cytokines were investigated using monoclonal antibodies and flow cytometry, production of extracellular cytokines was measured using enzyme-linked immunosorbent assay kits.The increase of total γδT cells number in patients with squamous cell carcinoma accompanied by changes in Vγ2+/Vγ1+T cells ratio in peripheral blood of both patients’ groups with malignant and benign nasal cavity and paranasal sinuses tumors were revealed as compared to healthy donors. The upregulated γδT cell response to phosphoantigen induction in combination with reduced indices of stimulations were shown in the both patients groups but cytokine profile was different, i.e., the elevated IFNγ production has been determined in patients with squamous cell carcinoma. However, in patients with inverted papilloma, redistribution of γδT cell subsets has been associated with IL-17-producing γδT cells. Moreover, the percent of IFNγ+γδT lymphocytes did correlate with IFNγ concentration in cell culture supernatants of patients with malignant nasal cavity and paranasal sinuses neoplasms (R = 0.61; p < 0.05).The revealed data suggest an involvement of γδT lymphocytes in malignant and benign tumor pathogenesis and may provide a fundamental basis for further detection of possible tumor-associated inflammation and malignization predictors.

Bifidobacterium species BB_003 enhances antitumor immunity in patients with NMIBC and improve recurrence-free survival

Bifidobacterium species BB_003 enhances antitumor immunity in patients with NMIBC and improve recurrence-free survival

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. A multicenter, retrospective-prospective Italian study. We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Cuproptosis-related immune checkpoint gene signature: Prediction of prognosis and immune response for hepatocellular carcinoma.

Immune checkpoint genes (ICGs), the foundation of immunotherapy, are involved in the incidence and progression of hepatocellular carcinoma (HCC). Cuproptosis is characterized by copper-induced cell death, and this novel cell death pathway has piqued the interest of researchers in recent years. It is worth noting that there is little information available in the literature to determine the relationship between cuproptosis and anti-tumor immunity. We identified 39 cuproptosis-related ICGs using ICGs co-expressed with cuproptosis-related genes. A prognostic risk signature was constructed using the Cox regression and the least absolute shrinkage and selection operator analysis methods. The signature was built using the Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma database. The TCGA and International Cancer Genome Consortium cohorts were classified into two groups; the low- and high-risk groups were determined using a prognostic signature comprised of five genes. The multivariate Cox regression analysis revealed that the signature could independently predict overall survival. Furthermore, the level of immune infiltration analysis revealed the robustness of the prognostic signature-immune cell infiltration relationship observed for Tregs, macrophages, helper T cells, and naive B cells. Both groups showed significant differences in immune checkpoint expression levels. The gene enrichment analysis was used for characterization, and the results revealed that enriching various pathways such as PI3K-AKT-mTOR signaling, glycolysis, Wnt/beta-catenin signaling, and unfolded protein response could potentially influence the prognosis of patients with HCC and the level of immune infiltration. The sensitivity of the two groups of patients to various drug-targeted therapy methods and immunotherapy was analyzed. In conclusion, the findings presented here lay the foundation for developing individualized treatment methods for HCC patients. The findings also revealed that studying the cuproptosis-based pathway can aid in the prognosis of HCC patients. It is also possible that cuproptosis contributes to developing anti-tumor immunity in patients.

Reprogramming the tumor microenvironment to improve the efficacy of cancer immunotherapies.

The immunotherapeutic approaches based on checkpoint inhibitors, tumor vaccination, immune cell-based therapy, and cytokines were developed to engage the patient's immune system against cancer and better survival of them. While potent, however, preclinical and clinical data have identified that abnormalities in the tumor microenvironment (TME) can affect the efficacy of immunotherapies in some cancers. It is therefore imperative to develop new therapeutic interventions that will enable to overcome tumor-supportive TME and restrain anti-tumor immunity in patients that acquire resistance to current immunotherapies. Therefore, recognition of the essential nature of the tolerogenic TME may lead to a shift from the immune-suppressive TME to an immune-stimulating phenotype. Here, we review the composition of the TME and its effect on tumor immunoediting and then present how targeted monotherapy or combination therapies can be employed for reprogramming educated TME to improve current immunotherapies outcomes or elucidate potential therapeutic targets.

Abstract 2899: Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors

Abstract Regulatory T cells (Tregs) contribute to immunosuppression within the tumor microenvironment and have been associated with poor outcomes in a range of cancers. Targeted depletion of tumor-infiltrating Tregs (TITRs) is an attractive therapeutic strategy with the potential to enhance antitumor immunity in patients who do not respond to current treatments. However, such approaches have been limited to date by a lack of markers that are highly specific for TITRs. CCR8 is a chemokine G protein-coupled receptor (GPCR) that has recently been shown to be specifically expressed on TITRs as compared to Tregs in the periphery or other T cells within tumors. Here, we report the development and characterization of HFB101110, a humanized monoclonal antibody against CCR8 with potent and specific antibody-dependent cellular cytotoxicity (ADCC) activity. HFB101110 specifically recognizes an epitope on the N-terminus extracellular domain of CCR8 and does not recognize the closely related chemokine receptor CCR4. HFB101110 acts through a dual mechanism of action, by both depleting CCR8+ cells via ADCC and blocking binding of the CCL1 chemokine to its receptor CCR8. Blockade by HFB101110 inhibited calcium flux and chemotaxis induced by the interaction between CCL1 and CCR8. Furthermore, HFB101110 showed potent single agent anti-tumor activity associated with depletion of intratumoral Tregs in a human CCR8 knock-in mouse model. HFB101110 mediated specific ex vivo killing of Tregs from primary patient tumor samples both in the presence, and in some cases the absence, of allogeneic NK cells. HFB101110 showed favorable pharmacokinetic properties and a favorable developability profile, and was well-tolerated in both wild-type mice and cynomolgus monkeys. HFB101110 is currently being developed as a novel immunotherapy for the treatment of solid tumors coupled with a patient biomarker strategy derived from HiFiBiO’s Drug Intelligent Science (DIS™) single-cell immune profiling platform. Citation Format: Roshan M. Kumar, Julie Prigent, Hombline Poullain, Ayrin Kok, Carine George, Sami Ellouze, Yun-Yueh Lu, Rebecca Silver, Clarisse Monchecourt, Ross B. Fulton, Qian Zhang, Nicola Beltraminelli, Bernhard Moser, Francisco Adrian, Liang Schweizer. Targeting regulatory T cells with HFB101110, a novel anti-human CCR8 antibody for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2899.

Defining the cooperation between T cell responses to MHC-I and MHC-II melanoma neoantigens towards developing effective personalized cancer immunotherapies.

Abstract Immune checkpoint therapy (ICT) (e.g. anti-CTLA-4, anti-PD-1) enables durable T-cell dependent anti-tumor immunity in patients with solid tumors. Since not all patients respond to ICT, this work aims at developing a more in-depth understanding of T-cell responses to MHC class I (MHC-I) and MHC class II (MHC-II) tumor antigens that occur as a consequence of aberrant expression of non-mutant antigens or driver and passenger mutations that form tumor neoantigens. We used a poorly immunogenic Brafv600e Pten−/−Cdkn2a−/− YUMM1.7 (Y1.7) murine melanoma line that with a paucity of endogenous neoantigens that is unresponsive to ICT, and introduced model neoantigens previously identified in a murine sarcoma tumor line expressing the same MHC haplotype as the Y1.7 line. The MHC-I neoantigen used was formed by a G1254V point mutation in the Laminin alpha subunit-4 (Lama4) and the MHC-II neoantigen was formed by an A710T point mutation in Integrin beta-1 (Itgb1). Anti-CTLA-4-treated mice bearing the parental Y1.7 melanoma displayed progressive tumor growth, whereas the modified Y1.7 line expressing mLama4 and mItgb1 (Y1.7.mLama4.mItgb1) was rendered sensitive to ICT. Preliminary data showed that anti-CTLA-4 treated Y1.7.mLama4.mItgb1 tumors reject in mice in a CD4+ T cell and CD8+ T cell-dependent manner. Additionally, intratumoral mLama4-specific CD8+ T cells were detected in anti-CTLA-4-treated Y1.7.mLama4.mItgb1 melanoma bearing mice. Overall this model will allow us to better understand T cell mediated anti-tumor responses to both MHC-I and MHC-II neoantigens, as well as shared, non-mutant melanoma antigens (e.g. Pmel/GP100 and Trp2), which may facilitate development of improved neoantigen-based personalized immunotherapies.

PD59-12 MICROWAVE ABLATION COMBINED WITH ANTI-PD-1/CTLA-4 THERAPY INDUCES ANTI-TUMOR IMMUNE RESPONSE TO RENAL CELL CARCINOMA IN A MURINE MODEL

You have accessJournal of UrologyCME1 May 2022PD59-12 MICROWAVE ABLATION COMBINED WITH ANTI-PD-1/CTLA-4 THERAPY INDUCES ANTI-TUMOR IMMUNE RESPONSE TO RENAL CELL CARCINOMA IN A MURINE MODEL Run-Qi Guo, Jin-Zhao Peng, and Xiao-Guang Li Run-Qi GuoRun-Qi Guo More articles by this author , Jin-Zhao PengJin-Zhao Peng More articles by this author , and Xiao-Guang LiXiao-Guang Li More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002644.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Our current study was designed to investigate the characteristics of immune responses induced by MWA and dual immune checkpoint inhibitors (ICIs) in tumor tissues from tumor-bearing mice, with purpose of providing new insight into immune suppressive mechanisms limiting MWA efficacy and exploring the potential of dual ICIs in combination with MWA in cancer therapy. METHODS: First, untreated tumor assessment was performed to determine whether untreated tumor growth was suppressed. Mice with tumors established on the left kidney and right flank were randomly divided into 4 groups: the control group, the MWA group, the ICI group, and the MWA+ ICI group. Then, a rechallenge test was performed to determine whether systemic anti-tumor immunity was established. RESULTS: Although the volume of the untreated tumors continued to increase, tumor growth rates in the ICI group and the MWA+ICI group were significantly lower. CD8+ T cells were only significantly higher in the MWA+ICI group, while Treg cells were significantly lower in the MWA group, the ICI group and the MWA+ICI group. The MWA+ICI group also showed the highest amount of IFN-γ. Histopathologic studies revealed that cytotoxic T lymphocyte-associated antigen 4 expression (CTLA-4) in the distant tumor was significantly lower in the ICI group and the MWA+ICI group. MWA treatment led to an increase in programmed death ligand 1 (PD-L1)/ programmed death receptor 1 (PD-1) expression; however, after combining with ICI treatment, the expression decreased. In the tumor rechallenge test, tumor rejection was apparent in 16.7% of the mice in the MWA group, 50% of the mice in the ICI group, and 66.7% of the mice in the MWA+ICI group, whereas no mice in the control group showed tumor rejection. CONCLUSIONS: This study demonstrated that MWA induced systemic anti-tumor immunity was enhanced by combined use of anti PD-1/CTLA-4 therapy in a murine RENCA tumor model. The mice that received the combination therapy showed suppression of untreated tumor growth and tumor rejection. This treatment regimen is a potential clinical approach to enhance systemic anti-tumor immunity in patients with metastatic renal cell carcinoma. Source of Funding: This study was supported by Beijing Hospital Scientific Research Starting Foundation for PhD/MD under Grant BJ-2019-135 to Dr. Guo © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1023 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Run-Qi Guo More articles by this author Jin-Zhao Peng More articles by this author Xiao-Guang Li More articles by this author Expand All Advertisement PDF DownloadLoading ...

A Mutated Prostatic Acid Phosphatase (PAP) Peptide-Based Vaccine Induces PAP-Specific CD8+ T Cells with Ex Vivo Cytotoxic Capacities in HHDII/DR1 Transgenic Mice

Simple SummaryTreatments for castrate (hormone)-resistant prostate cancer (CRPC) remain limited and are not curative. Although the first (and only) FDA-approved vaccine for CRPC (PROVENGE®, Sipuleucel-T) has been shown to improve the overall survival of patients, it is not curative and its cost prevents its widespread use. PROVENGE® induces immunity to prostatic acid phosphatase (PAP), a protein which is highly expressed in prostate cancer (PCa). Herein, we have developed a new PAP-based vaccine for PCa and demonstrated the presence of circulating PAP-specific CD8+ T cells that are responsive to this vaccine in patients with PCa. We have also shown that this new PAP sequence-derived peptide containing a modified amino sequence, in association with a strong adjuvant called CAF®09, induces strong immune responses and cytotoxic potential in a murine HHDII/DR1 transgenic model.Background: Current treatments for castrate (hormone)-resistant prostate cancer (CRPC) remain limited and are not curative, with a median survival from diagnosis of 23 months. The PAP-specific Sipuleucel-T vaccine, which was approved by the FDA in 2010, increases the Overall Survival (OS) by 4 months, but is extremely expensive. We have previously shown that a 15 amino accid (AA) PAP sequence-derived peptide could induce strong immune responses and delay the growth of murine TRAMP-C1 prostate tumors. We have now substituted one amino acid and elongated the sequence to include epitopes predicted to bind to several additional HLA haplotypes. Herein, we present the immunological properties of this 42mer-mutated PAP-derived sequence (MutPAP42mer). Methods: The presence of PAP-135-143 epitope-specific CD8+ T cells in the blood of patients with prostate cancer (PCa) was assessed by flow cytometry using Dextramer™ technology. HHDII/DR1 transgenic mice were immunized with mutated and non-mutated PAP-derived 42mer peptides in the presence of CAF®09 or CpG ODN1826 (TLR-9 agonist) adjuvants. Vaccine-induced immune responses were measured by assessing the proportion and functionality of splenic PAP-specific T cells in vitro. Results: PAP-135-143 epitope-specific CD8+ T cells were detected in the blood of patients with PCa and stimulation of PBMCs from patients with PCa with mutPAP42mer enhanced their capacity to kill human LNCaP PCa target cells expressing PAP. The MutPAP42mer peptide was significantly more immunogenic in HHDII/DR1 mice than the wild type sequence, and immunogenicity was further enhanced when combined with the CAF®09 adjuvant. The vaccine induced secretory (IFNγ and TNFα) and cytotoxic CD8+ T cells and effector memory splenic T cells. Conclusions: The periphery of patients with PCa exhibits immune responsiveness to the MutPAP42mer peptide and immunization of mice induces/expands T cell-driven, wild-type PAP immunity, and therefore, has the potential to drive protective anti-tumor immunity in patients with PCa.

USH2A Mutation is Associated With Tumor Mutation Burden and Antitumor Immunity in Patients With Colon Adenocarcinoma.

Colon adenocarcinoma (COAD) is one of the diseases with the highest morbidity and mortality in the world. At present, immunotherapy has become a valuable method for the treatment of COAD. Tumor mutational burden (TMB) is considered to be the most common biomarker for predicting immunotherapy. According to reports, the mutation rate of COAD ranks third. However, whether these gene mutations are related to TMB and immune response is still unknown. Here, COAD somatic mutation data were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Bioinformatics methods were used to study the relationships among gene mutations, COAD survival prognosis, and tumor immune response. A total of 22 of the top 40 mutations in TCGA and ICGC databases were the same. Among them, the USH2A mutation was associated with high TMB and poor clinical prognosis. According to Gene Set Enrichment Analysis (GSEA) and the CIBERSORT algorithm, we determined that the USH2A mutation upregulates signaling pathways involved in the immune system and the antitumor immune response. In cases with a USH2A mutation, the immune score and MSI score of TCGA samples increased, the expression of immune checkpoint genes decreased significantly, and the TIDE score decreased significantly. Dependent on the presence or absence of a USH2A mutation, TCGA COAD samples were analyzed for differentially expressed genes, 522 of which were identified. Using a univariate Cox analysis and LASSO COX analysis of these differential genes, a prediction model was established, which established significant differences in the infiltration of immune cells, immune checkpoint gene expression, immune score, MSI score, TMB, and TIDE in patients in high- and low-risk groups. In conclusion, mutation of USH2A is frequent in COAD and is related to an increase in TMB and the antitumor immunity. The differential genes screened by USH2A mutation allowed the construction of a risk model for predicting the survival and prognosis of cancer patients, in addition to providing new ideas for COAD immunotherapy.

Abstract 1505: Reprogramming cancer into antigen presenting cells as a novel immunotherapy

Abstract As a therapeutic modality, cancer vaccination leverages the well-characterized ability of antigen presenting cells (APCs) to take up and present tumor antigens in an effort to stimulate potent anti-cancer T cell responses. However, clinical successes with therapeutic cancer vaccination remains limited. Here, we present a novel cancer vaccination approach utilizing myeloid lineage reprogramming to directly convert cancer cells into tumor reprogramed-APCs (TR-APCs).In order to understand the therapeutic potential of TR-APCs, we generated syngeneic murine B-cell acute lymphoblastic leukemia models amenable to myeloid lineage reprogramming via ectopic expression of the myeloid lineage transcription factors PU.1 (Spi1) and C/EBPα (CEBPA). Upon enforced expression of these factors, the resulting TR-APCs acquire both myeloid phenotype and function, including the capacity for phagocytosis and antigen presentation. Crucially, TR-APCs can present endogenous self-derived tumor antigens directly encoded in their genome, without the need for phagocytosis and processing of adjacent tumor cells. In vitro, leukemia-derived TR-APCs express enhanced levels of antigen presentation machinery and co-stimulatory molecules, and potently stimulate tumor-specific CD4+ and CD8+ T cells. While in vivo TR-APC induction elicits only a modest extension to overall survival in immunodeficient hosts, generation of TR-APCs in immunocompetent syngeneic animals leads to complete leukemia eradication and protection from subsequent re-challenge. Further analysis of the in vivo immunological response to TR-APC induction revealed oligoclonal T cell expansion and establishment of cancer-specific immunological memory. Strikingly, use of a dual flank tumor model revealed that local TR-APC induction is sufficient to elicit systemic immunity capable of eradicating distant metastatic sites. We extended this treatment modality beyond hematologic malignancies, demonstrating that some solid tumors, including sarcomas and carcinomas, are amenable to myeloid-lineage reprogramming into TR-APCs, and contribute to increased overall survival. Finally, we demonstrate the clinical applicability of this approach by generating TR-APCs from primary human B cell acute lymphoblastic leukemia (B-ALL) specimens. Strikingly, primary B-ALL-derived TR-APCs stimulate autologous patient-derived T cells, demonstrating the clinical potential of TR-APCs to enhance antitumor immunity in patients. Thus, TR-APCs represent a novel cancer vaccination therapeutic strategy with broad implications for clinical immuno-oncology. Citation Format: Miles H. Linde, Sarah F. Gurev, Paul Phan, Feifei Zhao, Eric J. Gars, Melissa Stafford, Thomas Köhnke, Payton L. Marshall, Amy C. Fan, Christopher G. Dove, Ian L. Linde, Lindsay P. Miller, Robbie G. Majzner, Tian Yi Zhang, Ravindra Majeti. Reprogramming cancer into antigen presenting cells as a novel immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1505.

Randomized phase II trial of a first-in-human cancer cell lysate vaccine in patients with thoracic malignancies.

BackgroundAlthough most malignancies express cancer-testis antigens (CTA), immune responses to these proteins are limited in thoracic oncology patients. This trial was undertaken to examine if a cancer cell lysate vaccine could induce immunity to CTA, and to ascertain if metronomic cyclophosphamide and celecoxib enhances vaccine-induced immune responses.MethodsEleven patients with primary thoracic malignancies and 10 patients with extrathoracic neoplasms metastatic to the chest rendered NED by conventional therapies were randomized to receive H1299 lung cancer cell lysates (10 mg protein/vaccine) with Iscomatrix™ adjuvant via deep intradermal injection q 4 weeks ×6 with or without daily oral metronomic cyclophosphamide/celecoxib. The primary endpoint was serologic response to purified CTA assessed 1 month after the 6th vaccination. Secondary endpoints included assessment of the effects of cyclophosphamide and celecoxib on frequency and magnitude of vaccine-induced immune responses to CTA. Exploratory endpoints included evaluation of the effects of the vaccine regimens on peripheral immune subsets. Standard of care imaging studies were obtained at baseline and 1 month after the 3rd and 6th vaccinations.ResultsAll patients exhibited local and systemic inflammatory responses lasting 72–96 hours following vaccinations. There were no dose limiting treatment related toxicities. Fourteen patients (67%) completed all six vaccinations. Eight of 14 patients (57%) exhibited serologic responses to NY-ESO-1. One patient developed antibodies to GAGE7; several patients exhibited reactivity to XAGE and MAGE-C2. Vaccine therapy decreased the percent of Tregs (P=0.0068), PD-1 expression on Tregs (P=0.0027), PD-L1 expression on CD14+ monocytes (P=0.0089), PD-L1 expression on classical monocytes (P=0.016), and PD-L1 expression on intermediate monocytes (P=0.0031). Cyclophosphamide/celecoxib did not appear to increase immune responses or enhance vaccine-induced alterations in peripheral immune subsets.ConclusionsH1299 lysate vaccines with Iscomatrix™ induce immune responses to CTA and modulate peripheral immune subsets in a manner that may enhance antitumor immunity in patients with thoracic malignancies.

Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma.

Simple SummaryPrimary central nervous system lymphoma is a rare disease with limited therapeutic options. A more profound understanding of the molecular mechanisms that underlie this disease has fostered the development of novel therapeutic approaches. Key developments for the treatment of primary central nervous system lymphoma were made in the field of small molecule inhibitors, i.e., drugs that were designed to specifically target the molecular backbone of cancer. Prominent examples include inhibitors of Bruton’s tyrosine kinase or mammalian target of rapamycin, as well as immune modulatory thalidomide analogues. Along the same lines, another major strain of drug development for primary central nervous system lymphoma comprises of immune checkpoint inhibitors, i.e., monoclonal antibodies designed to unleash anti-cancer immune reactions. This review article discusses these ongoing clinical developments, including biological rationale as well as preliminary toxicity and efficacy, and provides an outlook for future developments.This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far, limited therapeutic options. Small molecule targeted tyrosine kinase inhibitors, immunomodulatory agents, and immune checkpoint inhibitors will be discussed. The mechanisms of action, results of completed clinical studies, ongoing clinical trials, and future perspectives are summarized. Among the most promising clinical developments in the field of CNS lymphomas is ibrutinib, an inhibitor of Bruton’s tyrosine kinase, which relays activation of nuclear factor kappa B upon integration of constitutive B cell receptor and Toll-like receptor signals. Down-stream of nuclear factor kappa B, the thalidomide analogs lenalidomide and pomalidomide exert immunomodulatory functions and are currently explored against CNS lymphomas. Finally, immune checkpoint inhibitors, such as drugs targeting the PD-1 pathway, may become novel therapeutic options to unleash anti-tumor immunity in patients with primary CNS lymphoma.

Treatment with pembrolizumab in combination with the oncolytic virus pelareorep promotes anti-tumor immunity in patients with advanced pancreatic adenocarcinoma.

4144 Background: Pelareorep is an intravenously delivered oncolytic reovirus that can induce a T-cell-inflamed phenotype in pancreatic ductal adenocarcinoma (PDAC). In prior studies, tumor tissue analysis from patients treated with pelareorep shows pelareorep replication, increased T cell infiltration, and upregulation of PD-L1. We hypothesized that pelareorep in combination with pembrolizumab in patients with PDAC would lead to improved responses and anti-tumor immunological changes within peripheral blood and tumor biopsies in responding patients. Methods: PDAC patients who progressed after first-line treatment received pelareorep at a dose of 4.5x1010 TCID50 IV on Days 1, 2, 3 & 8 of Cycle (C) 1, and Days 1 & 8 with C2 onwards. Pembrolizumab was administered on Day 1 of each 21-day cycle at 200 mg IV. The primary objective was overall response rate by RECIST v 1.1 criteria. Secondary objectives included evaluating immunological changes within tumor tissue and peripheral blood, performed by multi-plex immunohistochemistry and spectral flow cytometry (Cytek), respectively. Results: Thirteen patients were enrolled. Disease control was achieved in 33% of the 12 efficacy-evaluable patients. One patient achieved a partial response (PR). Three additional patients achieved stable disease (SD). On-treatment tumor biopsies, collected during C1, showed pelareorep replication, increased infiltration of CD8+ T cells and PD-L1+ cells, and decreased expression of VDAC1, a mitochondrial gatekeeper for tumor promotion, relative to archival tissue. Reduced infiltration of Foxp3+ regulatory T cells (Treg) was observed in patients showing tumor response. Peripheral blood was collected at day 1 of each cycle and on C1 day 8. Relative to pretreatment samples, the number of CD8+ effector memory T cells and B cells tend to increase while the number of Treg cells declined in C2 onwards in patients with tumor response. Furthermore, these patients had increased expression of the mitochondrial protein TOMM20 in CD8+ T cells and decreased expression of PD-1 and the H3K27me3 epigenetic mark in Treg. Treatment was well tolerated with most treatment-related adverse events, including flu-like symptoms, being grade 1 or 2. Conclusions: The combination of pelareorep and pembrolizumab showed a manageable safety profile and modest efficacy in an unselected PDAC population. Additional correlation analyses between treatment efficacy and immunological changes will be presented. The anti-tumor activity of pelareorep and checkpoint blockade therapy is being evaluated further in additional ongoing studies. Clinical trial information: NCT03723915.