Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer

Càncer de pròstata; Metàstasi neoplàsica; ImmunoteràpiaCáncer de próstata; Metástasis neoplásica; InmunoterapiaProstate cancer; Metastatic neoplasm; ImmunotherapyPURPOSE PROSTVAC, a viral vector–based immunotherapy, prolonged median overall survival (OS) by 8.5 months versus placebo in metastatic castration-resistant prostate cancer in a phase II study. This phase III study further investigated those findings. PATIENTS AND METHODS Patients were randomly assigned to PROSTVAC (Arm V; n = 432), PROSTVAC plus granulocyte-macrophage colony-stimulating factor (Arm VG; n = 432), or placebo (Arm P; n = 433), stratified by prostate-specific antigen (less than 50 ng/mL v 50 ng/mL or more) and lactate dehydrogenase (less than 200 v 200 U/L or more). Primary end point was OS. Secondary end points were patients alive without events (AWE)—namely, radiographic progression, pain progression, chemotherapy initiation, or death—at 6 months and safety. The study design was a superiority trial of PROSTVAC (Arm V or Arm VG) versus Arm P. Three interim analyses were planned. RESULTS At the third interim analysis, criteria for futility were met and the trial was stopped early. Neither active treatment had an effect on median OS (Arm V, 34.4 months; hazard ratio, 1.01; 95% CI, 0.84 to 1.20; P = .47; Arm VG, 33.2 months; hazard ratio, 1.02; 95% CI, 0.86 to 1.22; P = .59; Arm P, 34.3 months). Likewise, AWE at 6 months was similar (Arm V, 29.4%; odds ratio, 0.96; 95% CI, 0.71 to 1.29; Arm VG, 28.0%; odds ratio, 0.89; 95% CI, 0.66 to 1.20; placebo, 30.3%). Adverse events were similar for the treatment and placebo groups, with the most common being injection site reactions (62% to 72%) and fatigue (21% to 24%). Arrhythmias were the most common cardiac-related events (1.4% to 3.5%). There were no reports of either myocarditis or pericarditis. Serious treatment-related events occurred in less than 1% of all patients. CONCLUSION Whereas PROSTVAC was safe and well tolerated, it had no effect on OS or AWE in metastatic castration-resistant prostate cancer. Combination therapy is currently being explored in clinical trials.Supported by Bavarian Nordic, the National Institute for Health Research Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust, and the Institute of Cancer Research. Funded in part by National Cancer Institute Cancer Center Support Grant No. P30-CA008748 and the Center for Cancer Research, National Cancer Institute.P30 CA008748/CA/NCI NIH HHS/United States DH_/Department of Health/United Kingdo

IgG Responses to Tissue-Associated Antigens as Biomarkers of Immunological Treatment Efficacy

We previously demonstrated that IgG responses to a panel of 126 prostate tissue-associated antigens are common in patients with prostate cancer. In the current report we questioned whether changes in IgG responses to this panel might be used as a measure of immune response, and potentially antigen spread, following prostate cancer-directed immune-active therapies. Sera were obtained from prostate cancer patients prior to and three months following treatment with androgen deprivation therapy (n = 34), a poxviral vaccine (n = 31), and a DNA vaccine (n = 21). Changes in IgG responses to individual antigens were identified by phage immunoblot. Patterns of IgG recognition following three months of treatment were evaluated using a machine-learned Bayesian Belief Network (ML-BBN). We found that different antigens were recognized following androgen deprivation compared with vaccine therapies. While the number of clinical responders was low in the vaccine-treated populations, we demonstrate that ML-BBN can be used to develop potentially predictive models

Analyses of 123 Peripheral Human Immune Cell Subsets: Defining Differences with Age and between Healthy Donors and Cancer Patients not Detected in Analysis of Standard Immune Cell Types

Recent advances in human immunology have led to the identification of novel immune cell subsets and the biological function of many of these subsets has now been identified. The recent US Food and Drug Administration approval of several immunotherapeutics for the treatment of a variety of cancer types and the results of ongoing immunotherapy clinical studies requires a more thorough interrogation of the immune system. We report here the use of flow cytometry-based analyses to identify 123 immune cell subsets of peripheral blood mononuclear cells. The use of these panels defines multiple differences in younger (< 40 years) vs. older (≥ 40 years) individuals and between aged-matched apparently healthy individuals and metastatic cancer patients, aspects not seen in the analysis of the following standard immune cell types: CD8, CD4, natural killer, natural killer-T, regulatory T, myeloid derived suppressor cells, conventional dendritic cells (DCs), plasmacytoid DCs and B cells. The use of these panels identifying 123 immune cell subsets may aid in the identification of patients who may benefit from immunotherapy, either prior to therapy or early in the immunotherapeutic regimen, for the treatment of cancer or other chronic or infectious diseases

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma.

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly

Samarium-153-EDTMP (Quadramet®) With or Without Vaccine in Metastatic Castration-Resistant Prostate Cancer: A Randomized Phase 2 Trial

PSA-TRICOM is a therapeutic vaccine in late stage clinical testing in metastatic castration-resistant prostate cancer (mCRPC). Samarium-153-ethylene diamine tetramethylene phosphonate (Sm-153-EDTMP; Quadramet®), a radiopharmaceutical, binds osteoblastic bone lesions and emits beta particles causing local tumor cell destruction. Preclinically, Sm-153-EDTMP alters tumor cell phenotype facilitating immune-mediated killing. This phase 2 multi-center trial randomized patients to Sm-153-EDTMP alone or with PSA-TRICOM vaccine. Eligibility required mCRPC, bone metastases, prior docetaxel and no visceral disease. The primary endpoint was the proportion of patients without radiographic disease progression at 4 months. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and immune responses. Forty-four patients enrolled. Eighteen and 21 patients were evaluable for the primary endpoint in Sm-153-EDTMP alone and combination arms, respectively. There was no statistical difference in the primary endpoint, with two of 18 (11.1%) and five of 21 (23.8%) in Sm-153-EDTMP alone and combination arms, respectively, having stable disease at approximately the 4-month evaluation time point (P = 0.27). Median PFS was 1.7 vs. 3.7 months in the Sm-153-EDTMP alone and combination arms (P = 0.041, HR = 0.51, P = 0.046). No patient in the Sm-153-EDTMP alone arm achieved prostate-specific antigen (PSA) decline \u3e 30% compared with four patients (of 21) in the combination arm, including three with PSA decline \u3e 50%. Toxicities were similar between arms and related to number of Sm-153-EDTMP doses administered. These results provide the rationale for clinical evaluation of new radiopharmaceuticals, such as Ra-223, in combination with PSA-TRICOM

Applications of large language models in cancer care: current evidence and future perspectives

The development of large language models (LLMs) is a recent success in the field of generative artificial intelligence (AI). They are computer models able to perform a wide range of natural language processing tasks, including content generation, question answering, or language translation. In recent months, a growing number of studies aimed to assess their potential applications in the field of medicine, including cancer care. In this mini review, we described the present published evidence for using LLMs in oncology. All the available studies assessed ChatGPT, an advanced language model developed by OpenAI, alone or compared to other LLMs, such as Google Bard, Chatsonic, and Perplexity. Although ChatGPT could provide adequate information on the screening or the management of specific solid tumors, it also demonstrated a significant error rate and a tendency toward providing obsolete data. Therefore, an accurate, expert-driven verification process remains mandatory to avoid the potential for misinformation and incorrect evidence. Overall, although this new generative AI-based technology has the potential to revolutionize the field of medicine, including that of cancer care, it will be necessary to develop rules to guide the application of these tools to maximize benefits and minimize risks

Magnetostriction of field-structured magnetoelastomers.

Field-structured magnetic particle composites are an important new class of materials that have great potential as both sensors and actuators. These materials are synthesized by suspending magnetic particles in a polymeric resin and subjecting these to magnetic fields while the resin polymerizes. If a simple uniaxial magnetic field is used, the particles will form chains, yielding composites whose magnetic susceptibility is enhanced along a single direction. A biaxial magnetic field, comprised of two orthogonal ac fields, forms particle sheets, yielding composites whose magnetic susceptibility is enhanced along two principal directions. A balanced triaxial magnetic field can be used to enhance the susceptibility in all directions, and biased heterodyned triaxial magnetic fields are especially effective for producing composites with a greatly enhanced susceptibility along a single axis. Magnetostriction is quadratic in the susceptibility, so increasing the composite susceptibility is important to developing actuators that function well at modest fields. To investigate magnetostriction in these field-structured composites we have constructed a sensitive, constant-stress apparatus capable of 1 ppm strain resolution. The sample geometry is designed to minimize demagnetizing field effects. With this apparatus we have demonstrated field-structured composites with nearly 10,000 ppm strain

If we build it they will come: targeting the immune response to breast cancer.

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance