Abstracts Of Clinical Trials Research Articles

Abstract 5010: Development of a universal cancer vaccine using common cancer antigens cocktail that targets various cancer patients and overcomes the heterogeneity of individual cancer

Abstract In clinical trials of the glypican-3 (GPC3)-derived peptide vaccine targeting hepatocellular carcinoma (HCC), hepatoblastoma, etc., peptide-specific CTL were detected in many patients. There have been some partial response advanced cancer cases, and it is expected to be effective in prolonging the prognosis after HCC surgery. Five children with refractory hepatoblastoma who had repeated relapses and remissions are all surviving for more than 9 years without relapse by only peptide vaccine therapy. On the other hand, several patients have experienced recurrence of hepatocellular carcinoma that does not express GPC3 despite the detection of a large number of peptide-specific CTLs in the blood after administration of peptide vaccines. GPC3 is highly expressed in many hepatocellular carcinomas, but there are GPC3-negative cancer cells, so it is difficult to prevent recurrence of hepatocellular carcinoma with a single type of GPC3 peptide vaccine. In other words, to cure cancer, it is necessary to combine multiple common cancer antigens. Through immunohistochemical analysis, we identified 10 common cancer antigens, including GPC3, that are frequently expressed in various solid cancers but rarely expressed in normal tissues. Five of these antigens are membrane protein antigens, and we have confirmed that at least one of these antigens, and often more than one, is expressed in many cancers investigated. We synthesized peptides predicted to be presented at HLA-A*24:02 or HLA-A*02:01 from the full-length amino acid sequences of 10 types of common cancer antigen proteins. These peptide vaccines were administered to HLA-A*24:02 or HLA-A*02:01 transgenic mice once a week for a total of three times, and a number of peptide-reactive CTLs were identified in the splenocytes. These peptides have better CTL-inducing ability than the peptides of the GPC3 peptide vaccine used in clinical trials. Among these 10 types of common cancer antigens, we will use 5 types of membrane protein common cancer antigens in particular to develop a cocktail mRNA vaccine with the goal of preventing cancer recurrence after surgery. Of course, it is also possible to develop cocktail peptide vaccines. At the same time, we are developing a cocktail CAR/TCR-T cell therapy targeting these common cancer antigens for the treatment of advanced cancer. Citation Format: Tetsuya Nakatsura, Kazumasa Takenouchi, Hiroki Kinoshita, Nobuo Tsukamoto, Kazunobu Ohnuki, Toshihiro Suzuki. Development of a universal cancer vaccine using common cancer antigens cocktail that targets various cancer patients and overcomes the heterogeneity of individual cancer [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 5010.

Trichotomization with two cutoff values using Kruskal-Wallis test by minimum P-value approach

Abstract In clinical trials, age is often converted to binary data by the cutoff value. However, when looking at a scatter plot for a group of patients whose age is larger than or equal to the cutoff value, age and outcome may not be related. If the group whose age is greater than or equal to the cutoff value is further divided into two groups, the older of the two groups may appear to be at lower risk. In this case, it may be necessary to further divide the group of patients whose age is greater than or equal to the cutoff value into two groups. This study provides a method for determining which of the two or three groups is the best split. The following two methods are used to divide the data. The existing method, the Wilcoxon-Mann-Whitney test by minimum P-value approach, divides data into two groups by one cutoff value. A new method, the Kruskal-Wallis test by minimum P-value approach, divides data into three groups by two cutoff values. Of the two tests, the one with the smaller P-value is used. Because this was a new decision procedure, it was tested using Monte Carlo simulations (MCSs) before application to the available COVID-19 data. The MCS results showed that this method performs well. In the COVID-19 data, it was optimal to divide into three groups by two cutoff values of 60 and 70 years old. By looking at COVID-19 data separated into three groups according to the two cutoff values, it was confirmed that each group had different features. We provided the R code that can be used to replicate the results of this manuscript. Another practical example can be performed by replacing x and y with appropriate ones.

Comparing the Value of Data Visualization Methods for Communicating Harms in Clinical Trials.

In clinical trials, harms (i.e., adverse events) are often reported by simply counting the number of people who experienced each event. Reporting only frequencies ignores other dimensions of the data that are important for stakeholders, including severity, seriousness, rate (recurrence), timing, and groups of related harms. Additionally, application of selection criteria to harms prevents most from being reported. Visualization of data could improve communication of multidimensional data. We replicated and compared the characteristics of 6 different approaches for visualizing harms: dot plot, stacked bar chart, volcano plot, heat map, treemap, and tendril plot. We considered binary events using individual participant data from a randomized trial of gabapentin for neuropathic pain. We assessed their value using a heuristic approach and a group of content experts. We produced all figures using R and share the open-source code on GitHub. Most original visualizations propose presenting individual harms (e.g., dizziness, somnolence) alone or alongside higher level (e.g., by body systems) summaries of harms, although they could be applied at either level. Visualizations can present different dimensions of all harms observed in trials. Except for the tendril plot, all other plots do not require individual participant data. The dot plot and volcano plot are favored as visualization approaches to present an overall summary of harms data. Our value assessment found the dot plot and volcano plot were favored by content experts. Using visualizations to report harms could improve communication. Trialists can use our provided code to easily implement these approaches.

Drug Susceptibility and Viral Fitness of HIV-1 with Integrase Strand Transfer Inhibitor Resistance Substitution Q148R or N155H in Combination with Nucleoside/Nucleotide Reverse Transcriptase Inhibitor Resistance Substitutions

In clinical trials of coformulated elvitegravir (EVG), cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF), emergent drug resistance predominantly involved the FTC resistance substitution M184V/I in reverse transcriptase (RT), with or without the tenofovir (TFV) resistance substitution K65R, accompanied by a primary EVG resistance substitution (E92Q, N155H, or Q148R) in integrase (IN). We previously reported that the RT-K65R, RT-M184V, and IN-E92Q substitutions lacked cross-class phenotypic resistance and replicative fitness compensation. As a follow-up, the in vitro characteristics of mutant HIV-1 containing RT-K65R and/or RT-M184V with IN-Q148R or IN-N155H were also evaluated, alone and in combination, for potential interactions. Single mutants displayed reduced susceptibility to their corresponding inhibitor classes, with no cross-class resistance. Viruses with IN-Q148R or IN-N155H exhibited reduced susceptibility to EVG (137- and 40-fold, respectively) that was not affected by the addition of RT-M184V or RT-K65R/M184V. All viruses containing RT-M184V were resistant to FTC (>1,000-fold). Mutants with RT-K65R had reduced susceptibility to TFV (3.3- to 3.6-fold). Without drugs present, the viral fitness of RT and/or IN mutants was diminished relative to that of the wild type in the following genotypic order: wild type > RT-M184V ≥ IN-N155H ≈ IN-Q148R ≥ RT-M184V + IN-N155H ≥ RT-M184V + IN-Q148R ≥ RT-K65R/M184V + IN-Q148R ≈ RT-K65R/M184V + IN-N155H. In the presence of drug concentrations approaching physiologic levels, drug resistance counteracted replication defects, allowing single mutants to outcompete the wild type with one drug present and double mutants to outcompete single mutants with two drugs present. These results suggest that during antiretroviral treatment with multiple drugs, the development of viruses with combinations of resistance substitutions may be favored despite diminished viral fitness.

Increased lymphopenia results in higher percentages of FoxP3+ T cells in patients reconstituted by PBMC adoptive transfer and vaccinated (41.36)

Abstract In clinical trials therapeutic tumor vaccines have failed to provide evidence of efficacy. Based on preclinical tumor models showing that vaccination during homeostasis-driven proliferation improved therapeutic efficacy, we performed a translational phase I/II clinical trial in men with metastatic hormone-refractory adenocarcinoma of the prostate. This strategy has the theoretical advantage that it eliminates regulatory T cells (Treg). Patients were randomized to cohort A, B or C. Cohort A patients (n = 5) received prostate GVAX TM (two prostate cancer cell lines that secrete GM-CSF, Cell Genesys Inc.) vaccination only. Cohort B (n = 5) received cyclophosphamide followed by reinfusion of autologous PBMC and vaccine (GVAX). Cohort C patients (n=5) received same treatment as Cohort B with the addition of fludarabine. We hypothesized that the most lymphopenic patients would have the fewest Treg. While all cohorts showed an increase in the total number and frequency of peripheral Treg, the most lymphopenic patients (cohort C) had the greatest fold increase in peripheral Treg at weeks 2-6 (2.3,1.2,0.7 / p<0.05). Current studies are examining whether adoptive transfer of CD25 depleted PBMC will reduce Treg recovery and improve clinical response. Supported by CA119123, Robert W. Franz, Chiles foundation, Prostate Cancer Foundation and Providence Medical Foundation

Public Disclosure in Research with Exception from Informed Consent: The Use of Survey Methods to Assess its Effectiveness

IN CLINICAL TRIALS WITH EXCEPTION from informed consent, the Final Rule stipulates that investigators inform and consult with the community. A random-digit-dialing survey of 200 individuals assessed the effectiveness of public disclosure via press releases, notices in local newspapers, local radio and television stations and the host hospital's website, as well as a series of community meetings regarding a pending clinical trial of this kind. Results showed a 10% awareness level of the public trial, which is higher than surveys using convenience samples. Understanding of the nature of the trial was generally poor, while opinions about participating in this type of research were more favorable among individuals aware of the trial. Our findings suggest that adherence to the intent of the Final Rule is dependent on uniform guidelines for what constitute effective public disclosure methods and adequate community awareness and understanding and the use of rigorous sampling methods for evaluation.