Citations

Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor-infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecologic system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

Abstract Background: In vivo synergy with concurrent PI3-Kinase inhibition and PARP inhibition has been observed in BRCA-deficient and BRCA-proficient preclinical models of triple negative breast cancer (TNBC) and ovarian cancer (OC). A phase I trial of the oral pan-class I PI3-Kinase inhibitor BKM120 and the PARP inhibitor olaparib demonstrated anti-cancer activity in TNBC and OC, both in patients with and without germline BRCA1 and BRCA2 (BRCA) mutations. However, CNS toxicity (depression) and liver function test abnormalities limited dose escalation of BKM120 prompting evaluation of the alpha specific PI3-Kinase inhibitor BYL719 (which has no CNS toxicity) in combination with olaparib. Methods: Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with primary objectives of defining the maximum tolerated dose (MTD) and recommended phase 2 dose of the combination of BYL719 and olaparib, and secondary objectives of defining toxicity, activity, and pharmacokinetic profiles of both agents. Eligibility included recurrent TNBC or high grade serous (HGS) OC, or any histology OC or breast cancer (BC) with presence of a known germline BRCA mutation, performance status of 0-1 and measurable/evaluable cancer. Patients with platinum sensitive or resistant or refractory OC were eligible and prior PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for both BC and OC. Results: 46 patients (16 BC and 30 OC) have been enrolled in the study; 28 patients participated in the dose escalation portion of the study (4 BC and 24 OC). Two patients with OC did not receive study drugs because of ineligibility. MTD was defined as BYL719 200mg once daily and olaparib 200mg twice daily. Dose limiting toxicities included hyperglycemia, rash and fever with decreased neutrophil count. Four patients (3 OC and 1 BC) discontinued protocol therapy because of toxicity (2 for hyperglycemia, 1 for nausea and 1 for allergic reaction). Most common toxicities included nausea, hyperglycemia, fatigue, diarrhea and vomiting. At the MTD, 6 patients with OC and 12 patients with BC were enrolled into a dose expansion cohort. The OC expansion cohort has completed enrollment, while the BC cohort is still enrolling. Among patients with OC who received study drugs (28 patients, 26 (93%) with platinum resistant disease), objective response rate (ORR) by RECIST 1.1 was 36% (10/28 patients, all partial responses (PRs)). Median duration of response was 167 days (range 16-398 days); 5 of 10 patients with PR remain on treatment. ORR was 33% for patients with germline BRCA mutations and 31% for patients without germline BRCA mutations. Among patients without germline BRCA mutations with platinum resistant OC, ORR was 29%. Conclusions: Combined BYL719 and olaparib is feasible, and similar clinical benefit was observed in patients with and without germline BRCA mutations. The activity of this combination in OC patients without germline BRCA mutations and with platinum resistant disease was higher than expected from olaparib monotherapy and warrants further investigation. This work was funded in part by the Stand Up To Cancer Ovarian Dream Team. Clinical trial: NCT01623349. Citation Format: Panagiotis A. Konstantinopoulos, William T. Barry, Michael Birrer, Shannon N. Westin, Sarah Farooq, Karen Cadoo, Christin Whalen, Weixiu Luo, Hui Liu, Carol Aghajanian, David B. Solit, Gordon B. Mills, Barry S. Taylor, Helen Won, Michael F. Berger, Sangeetha Palakurthi, Joyce F. Liu, Lew Cantley, Scott H. Kaufmann, Elizabeth M. Swisher, Alan D. D'Andrea, Eric Winer, Gerburg M. Wulf, Ursula A. Matulonis. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT008. doi:10.1158/1538-7445.AM2017-CT008

Abstract The hematological malignancy acute myeloid leukemia (AML) interacts closely with osteoblasts within the protective bone marrow microenvironment. The bone marrow microenvironment protects tumor cells from chemotherapies, which can prevent sufficient eradication of tumor cells. To study the role of osteoblasts in the bone marrow microenvironment, our lab utilized a co-culture model of osteoblasts (MC3T3 osteoblast cell line) and acute myelogenous leukemia cells (KG1a AML cell line or AML patient samples from bone marrow aspirates). Osteoblasts were cultured with AML cells, or AML cells were cultured alone; AML cells were challenged with the standard chemotherapeutic agent cytarabine (Ara-C) at doses of 0µM, 0.1µM, 0.5µM, 1µM, 5µM, or 10µM in the presence or absence of osteoblasts; and AML cells were assayed by flow cytometry to assess cell death via annexin-V staining. Our lab has previously found that differentiating osteoblasts protect AML cells from an apoptosis inducing agent naturally present in the bone marrow. We now show that osteoblasts are also capable of protecting AML cells from the standard chemotherapeutic cytarabine. In addition, we have found that treatment of osteoblasts with the histone deacetylase inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) prevents these treated osteoblasts from protecting AML cells from cytarabine treatment, which is consistent with our lab’s previous findings that HDACi treatment inhibits protection of AML cells from an apoptosis inducing agent naturally present in the bone marrow. We have preliminary data that indicates that TAZS89A over-expression, a constitutively active form of TAZ, which is a transcriptional modulator that regulates osteoblast differentiation, may be sufficient to inhibit osteoblast mediated protection of AML cells from cytarabine. This finding would be consistent with the HDACi manipulated Nherf1-protein phosphatase 1α-TAZ signaling pathway that we have previously found to be sufficient to inhibit protection of AML cells from an apoptosis inducing agent naturally present in the bone marrow. Overall, these studies have delivered insights into the role of osteoblasts in protecting AML cells from chemotherapy in the bone marrow microenvironment and begun the characterization of mechanisms and targets responsible for the protective effects of osteoblasts. Manipulating differentiating osteoblasts within the bone marrow microenvironment therapeutically could aid in more complete destruction of the tumor cell burden and improve patient survival. Citation Format: Rosalie M. Sterner, Kimberly N. Kremer, Amel Dudakovic, Jennifer J. Westendorf, Andre J. van Wijnen, Karen E. Hedin. Osteoblasts protect AML cells from cytarabine-induced death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5930. doi:10.1158/1538-7445.AM2017-5930

Abstract Addressing underrepresentation of minorities and women as research participants has largely focused on clinical trials, while little is known about attitudes and knowledge regarding other types of biomedical research, e.g., epidemiologic and genetic studies. These types of studies are essential for advances in cancer research, including development of targeted therapies for women and minorities. As part of an academic/community partnership between Mayo Clinic and The Links, Incorporated, a national volunteer service organization of professional African American women, this study sought to: (1) examine attitudes regarding participation in research involving access to the medical record, genetic studies/biobanking, and clinical trials; and (2) develop and evaluate a novel, targeted online educational program addressing these 3 types of biomedical research. Initial qualitative inquiry via 3 focus groups (n=34) found that most women associated health-related research with clinical trials; few women were familiar with other study types. Women expressed more concerns about how information is collected, used, and shared by investigators than with personal mistreatment in research regardless of study type (genetic research (GEN), chart review (CR), clinical trial (CT)) or the kind of information (social, health, genetic) collected. The importance of investigator transparency regarding the significance of the disease in African Americans, research funding source, the investigator’s agenda, and commitment to the population being studied was emphasized. Qualitative results informed development of the educational program. A total of 244 Links members completed the program (77% response rate) and answered pre- and post-assessments of intentions, attitudes and knowledge. The percent of women indicating that they “definitely” or “probably” intend to participate in research increased from 9.4% to 19.5% and 27.1% to 49.8%, respectively, after program completion. Agreement with the statement “research in the U.S. is ethical” increased from 52.9% to 74.4%. Factual knowledge related to each of the 3 study types also increased. Prior to completing the program many women reported “little or no understanding” of the 3 types of studies (66% GEN, 62.9% CR, 40.7% CT) whereas after program completion, these numbers decreased to 24.9%, 18.4%, and 15.5%, respectively. While few women rated their opinion of the study types as “very positive” prior to beginning the program (14.3% GEN, 15.0% CR, 28.6% CT), upon completion these proportions increased and equalized (42.8% GEN, 43.0% CR, 42.5% CT). Two-month follow-up will evaluate longer-term impact including knowledge dissemination, visiting clinicaltrials.gov, and enrolling in ResearchMatch. An online education-to-action program targeting professional African American women improved knowledge, perceptions of research ethics, and intent to participate in biomedical research. Citation Format: Carmen Radecki Breitkopf, Karen P. Williams, Jennifer L. Ridgeway, Alice L. Strong Simmons, Monica W. Parker, Michele Y. Halyard, Sharonne N. Hayes. Linking education to action: A program to increase research participation among African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4233. doi:10.1158/1538-7445.AM2017-4233

While the clinicopathologic features of pediatric vestibular schwannomas, often in the context of neurofibromatosis type 2 (NF2), have been well studied, there is less data regarding the characteristics of pediatric non-vestibular schwannomas (NVS). Additionally, the rate of loss of SMARCB1/INI1 expression in this population has not been systematically evaluated. Our institutional archives were searched for cases of NVS arising in patients 18 years or younger. Clinicopathologic features including SMARCB1/INI1 status were assessed for each case. Twenty-three NVS from 9 males and 13 females (age range, 2 months to 18 years) were identified, and sites included paraspinal (n = 10), head and neck (n = 6), extremities (n = 4), trunk (n = 1), mediastinum (n = 1), and retroperitoneum (n = 1); 22 cases were Antoni A predominant with 6 cases comprising solely Antoni A tissue. The mitotic rate of the tumors ranged from 0 to 10/10 high-power fields (HPFs), and 3 tumors had mitotic rates of ≥4 mitoses/10 HPFs. Two tumors showed plexiform architecture. No NVS showed diffuse atypia, calcifications, microcystic/reticular architecture, epithelioid morphology, pseudoglandular change, neuroblastoma-like features, or necrosis. All tumors tested (23/23) showed retained nuclear expression of SMARCB1/INI1. Follow-up was available in 21 patients (range 1 week to 194 months), and 5 tumors recurred. Pediatric NVS have a relatively homogeneous appearance with a predominance of Antoni A areas. Pathologists should be aware that schwannomas in this age group may be cellular with mitotic rates of ≥4/10 HPFs to avoid misclassification as a spindle cell sarcoma.

Key Points T-cell activation induces TCR transactivation of CXCR4 to stabilize cytokine mRNA transcripts via a PREX1-Rac1–signaling pathway. Inhibition of the TCR-CXCR4–signaling pathway impairs TCR-dependent and TCR-independent cytokine secretion by CTCL cells.

Key Points Over the last decade, allogeneic HCT has been increasingly administered in the United States to adults aged 70 and older with hematologic malignancies. Allogeneic transplant outcomes were reasonable; high comorbidity and ablative conditioning regimens were associated with inferior outcomes.