PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.

BACKGROUND: Somatic mutations have the potential to encode "non-self" immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS: We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti-programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair-deficient colorectal cancers, patients with mismatch repair-proficient colorectal cancers, and patients with mismatch repair-deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS: The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair-deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair-proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair-deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair-proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P=0.05]). Patients with mismatch repair-deficient noncolorectal cancer had responses similar to those of patients with mismatch repair-deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair-deficient tumors, as compared with 73 in mismatch repair-proficient tumors (P=0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P=0.02). CONCLUSIONS: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

Translation of Evidence-Based Interventions Into Oncology Care Settings: An Integrative Review.

BACKGROUND: Adoption of evidence remains slow, leading to variations in practices and quality of care. Examining evidence-based interventions implemented within oncology settings can guide knowledge translation efforts. OBJECTIVE: This integrative review aimed to (1) identify topics implemented for oncology-related evidence-based practice (EBP) change; (2) describe frameworks, guidelines, and implementation strategies used to guide change; and (3) evaluate project quality. METHODS: PubMed and CINAHL were searched to identify published practice change projects. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were followed. Fifty articles met the inclusion criteria. Data were extracted; content analysis was conducted. The Quality Improvement Minimum Quality Criteria Set guided quality assessment. RESULTS: Topics included infection control/prevention (n = 18), pain/palliative care (n = 13), psychosocial assessment (n = 11), and medication adherence (n = 8). Among the projects, Plan, Do, Study, Act (n = 8) and Lean Six Sigma (n = 6) frameworks were used most. Thirty-six projects identified guidelines that directed interventions. Multiple implementation strategies were reported in all articles with planning, education, and restructuring the most common. Reach, sustainability, and ability to be replicated were identified as quality gaps across projects. CONCLUSION: The EBP topics that emerged are consistent with the oncology nursing priorities, including facilitating integration of EBP into practice. The studies identified used national guidelines and implementation strategies to move evidence into practice. Heterogeneity in measurement made synthesis of findings difficult across studies, although individual studies showed improvement in patient outcomes. IMPLICATIONS FOR PRACTICE: Development of an interprofessional oncology consortium could facilitate a standardized approach to implementation of high-priority topics that target improved patient outcomes, harmonize measures, and accelerate translation of evidence into practice.

A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma. A Phase II trial of safety, efficacy, and immune activation.

PURPOSE: Surgical resection provides the only possibility of cure for pancreas cancer. A standard adjuvant approach has not been established. We tested the safety and efficacy of a granulocyte-macrophage colony-stimulating factor (GM-CSF)-based immunotherapy administered in patients with resected pancreatic adenocarcinoma. PATIENTS AND METHODS: A single institution phase II study of 60 patients with resected pancreatic adenocarcinoma was performed. Each immunotherapy treatment consisted of a total of 5 × 108 GM-CSF-secreting cells distributed equally among 3 lymph node regions. The first immunotherapy treatment was administered 8 to 10 weeks after surgical resection. Subsequently, patients received 5-FU based chemoradiation. Patients who remained disease-free after completion of chemoradiotherapy received treatments 2 to 4, each 1 month apart. A fifth and final booster was administered 6 months after the fourth immunotherapy. The primary endpoint was disease free survival and secondary endpoints were overall survival and toxicity, and the induction of mesothelin specific T cell responses. RESULTS: The median disease-free survival is 17.3 months (95% CI, 14.6-22.8) with median survival of 24.8 months (95% CI, 21.2-31.6). The administration of immunotherapy was well tolerated. In addition, the post-immunotherapy induction of mesothelin-specific CD8+ T cells in HLA-A1+ and HLA-A2+patients correlates with disease-free survival. CONCLUSIONS: An immunotherapy approach integrated with chemoradiation is safe and demonstrates an overall survival that compares favorably with published data for resected pancreas cancer. These data suggest additional boost immunotherapies given at regular intervals beyond 1 year postsurgery should be tested in future studies, and provide the rationale for conducting a multicenter phase II study.

Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation.

PURPOSE: The combination of chemotherapy and immunotherapy has not been examined in patients with advanced pancreatic cancer. We conducted a study of two granulocyte macrophage colony-stimulating factor-secreting pancreatic cancer cell lines (CG8020/CG2505) as immunotherapy administered alone or in sequence with cyclophosphamide in patients with advanced pancreatic cancer. EXPERIMENTAL DESIGN: This was an open-label study with two cohorts: cohort A, 30 patients administered a maximum of six doses of CG8020/CG2505 at 21-day intervals; and cohort B, 20 patients administered 250 mg/m(2) of cyclophosphamide i.v. 1 day before the same immunotherapy given as in cohort A. The primary objective was to evaluate safety and duration of immunity. Secondary objectives included time to disease progression and median overall survival. RESULTS: The administration of CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity. Median survival values in cohort A and cohort B were 2.3 and 4.3 months, respectively. CD8(+) T-cell responses to HLA class I-restricted mesothelin epitopes were identified predominantly in patients treated with cyclophosphamide + CG8020/CG2505 immunotherapy. CONCLUSION: Granulocyte macrophage colony-stimulating factor-secreting pancreatic cancer cell lines CG8020/CG2505 alone or in sequence with cyclophosphamide showed minimal treatment-related toxicity in patients with advanced pancreatic cancer. Also, mesothelin-specific T-cell responses were detected/enhanced in some patients treated with CG8020/CG2505 immunotherapy. In addition, cyclophosphamide-modulated immunotherapy resulted in median survival in a gemcitabine-resistant population similar to chemotherapy alone. These findings support additional investigation of cyclophosphamide with CG8020/CG2505 immunotherapy in patients with advanced pancreatic cancer.

Homeless With Cancer: An Unrecognized Problem in the United States.

Homelessness is a national problem that is worsening. Some challenges the homeless face-lack of shelter, food, health care, support, and opportunities-are well known. Cancer, an unrecognized problem among the homeless, is a leading cause of their deaths.

Phase I/II trial of an allogeneic cellular immunotherapy in hormone-naïve prostate cancer.

PURPOSE: To determine the toxicity, immunologic, and clinical activity of immunotherapy with irradiated, allogeneic, prostate cancer cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) in patients with recurrent prostate cancer. PATIENTS AND METHODS: A single-institution phase I/II trial was done in hormone therapy-naïve patients with prostate-specific antigen (PSA) relapse following radical prostatectomy and absence of radiologic metastases. Treatments were administered weekly via intradermal injections of 1.2 x 10(8) GM-CSF gene-transduced, irradiated, cancer cells (6 x 10(7) LNCaP cells and 6 x 10(7) PC-3 cells) for 8 weeks. RESULTS: Twenty-one patients were enrolled and treated. Toxicities included local injection-site reactions, pruritus, and flu-like symptoms. One patient had a partial PSA response of 7-month duration. At 20 weeks post first treatment, 16 of 21 (76%) patients showed a statistically significant decrease in PSA velocity (slope) compared with prevaccination (P < 0.001). Injection site biopsies showed intradermal infiltrates consisting of CD1a+ dendritic cells and CD68+ macrophages, similar to previous clinical trials using autologous GM-CSF-transduced cancer cells. Posttreatment, patients developed new oligoclonal antibodies reactive against at least five identified antigens present in LNCaP or PC-3 cells. A high-titer antibody response against a 250-kDa antigen expressed on normal prostate epithelial cells was induced in a patient with partial PSA remission; titers of this antibody decreased when treatment ended, and subsequent PSA relapse occurred. CONCLUSIONS: This non-patient-specific prostate cancer immunotherapy has a favorable safety profile and is immunologically active. Continued clinical investigation at higher doses and with longer boosting schedules is warranted.

Immune reconstitution: the foundation for safe living after an allogeneic hematopoietic stem cell transplantation.

With increasing frequency, oncology nurses are providing long-term care to hematopoietic stem cell transplantation (HSCT) recipients in nontransplantation settings. This may be a result of more patients receiving HSCTs, recipients living longer, and recipients' desire to return to their hometowns as soon as possible. Although critical to patients' initial recovery after HSCT, immune reconstitution also must remain a priority of oncology nursing care long beyond the date of discharge from a transplantation center. As patients resume their normal lives, oncology nurses need to be diligent in assessment and education to facilitate the ultimate goal, a safe life after HSCT. This article provides concise details about the short- and long-term immunologic effects of HSCT and focuses on the long-standing threat of opportunistic infections that can persist months and years after HSCT.

Development of a cytokine-modified allogeneic whole cell pancreatic cancer vaccine.

The management of patients with pancreatic cancer is a multidisciplinary approach that presents enormous challenges to the clinician. Overall 5-yr survival for all patients remains < 3%. Symptoms of early pancreas cancer are nonspecific. As such, only a fraction of patients are candidates for surgery. While surgical resection provides the only curative option, most patients will develop tumor recurrence and die of their disease. To date, the clinical benefits of chemotherapy and radiation therapy have been important but have led to modest improvements. Tumor vaccines have the potential to specifically target the needle of pancreas cancer cells amidst the haystack of normal tissue. The discovery of pancreas tumor-specific antigens and the subsequent ability to harness this technology has become an area of intense interest for tumor immunologists and clinicians alike. Without knowledge of specific antigen targets, the whole tumor cell represents the best source of immunizing antigens. This chapter will focus on the development of whole tumor cell vaccine strategies for pancreas cancer.

Development of a cytokine-modified allogeneic whole cell pancreatic cancer vaccine.

Management of patients with pancreatic cancer is a multidisciplinary approach that presents enormous challenges to the clinician. Overall 5-year survival for all patients remains <3%. Symptoms of early pancreas cancer are nonspecific. As such, only a fraction of patients are candidates for surgery. While surgical resection provides the only curative option, most patients will develop tumor recurrence and die of their disease. To date, the clinical benefits of chemotherapy and radiation therapy have been important but have led to modest improvements. Tumor vaccines have the potential to specifically target the needle of pancreas cancer cells amidst the haystack of normal tissue. The discovery of pancreas tumor-specific antigens and the subsequent ability to harness this technology has become an area of intense interest for tumor immunologists and clinicians alike. Without knowledge of specific antigen targets, the whole tumor cell represents the best source of immunizing antigens. This chapter will focus on the development of whole tumor cell vaccine strategies for pancreas cancer.

Research information knowledge, perceived adequacy, and understanding in cancer clinical trial participants.

PURPOSE/OBJECTIVES: To describe the adequacy of research information among people with cancer at the time they accept or decline participation in a cancer clinical trial. DESIGN: Cross-sectional, descriptive. SETTING: An urban, academic, National Cancer Institute-designated comprehensive cancer center. SAMPLE: 197 patients with advanced gastrointestinal cancer. METHODS: Mailed survey; self-reported data. MAIN RESEARCH VARIABLES: Adequacy of research information (actual knowledge, perceived adequacy of information, and perceived understanding), cancer clinical trial participation, and satisfaction with the decision to participate. FINDINGS: Most respondents (88%) perceived themselves as having adequate information to make an informed decision regarding cancer clinical trial participation. In addition, 35% demonstrated adequate knowledge of basic clinical research. CONCLUSIONS: Patients decide to accept or decline cancer clinical trials without having adequate knowledge. IMPLICATIONS FOR NURSING: Nurses have an important role in educating patients regarding cancer clinical trials. The ideal teachable moment may not occur at the time of diagnosis; other less stressful opportunities may present when the patient is more receptive.

Factors and outcomes of decision making for cancer clinical trial participation.

PURPOSE/OBJECTIVES: To describe factors and outcomes related to the decision-making process regarding participation in a cancer clinical trial. DESIGN: Cross-sectional, descriptive. SETTING: Urban, academic, National Cancer Institute-designated comprehensive cancer center in the mid-Atlantic United States. SAMPLE: 197 patients with advanced gastrointestinal cancer. METHODS: Mailed survey using one investigator-developed instrument, eight instruments used in published research, and a medical record review. INDEPENDENT VARIABLES: disease context, sociodemographics, hope, quality of life, trust in healthcare system, trust in health professional, preference for research decision control, understanding risks, and information. DEPENDENT VARIABLES: decision to accept or decline research participation and satisfaction with this decision. FINDINGS: All of the factors within the Research Decision Making Model together predicted cancer clinical trial participation and satisfaction with this decision. The most frequently preferred decision-making style for research participation was shared (collaborative) (83%). CONCLUSIONS: Multiple factors affect decision making for cancer clinical trial participation and satisfaction with this decision. Shared decision making previously was an unrecognized factor and requires further investigation. IMPLICATIONS FOR NURSING: Enhancing the process of research decision making may facilitate an increase in cancer clinical trial enrollment rates. Oncology nurses have unique opportunities as educators and researchers to support shared decision making by those who prefer this method for deciding whether to accept or decline cancer clinical trial participation.