Optimizing the Therapeutic Window of Targeted Drugs in Oncology: Potency-Guided First-in-Human Studies.

Many targeted therapies are administered at or near the maximum tolerated dose (MTD). With the advent of precision medicine, a larger therapeutic window is expected. Therefore, dose optimization will require a new approach to early clinical trial design. We analyzed publicly available data for 21 therapies targeting six kinases, and four poly (ADP-ribose) polymerase inhibitors, focusing on potency and exposure to gain insight into dose selection. The free average steady-state concentration (Css ) at the approved dose was compared to the in vitro cell potency (half-maximal inhibitory concentration (IC50 )). Average steady-state area under the plasma concentration-time curve, the fraction unbound drug in plasma, and the cell potency were taken from the US drug labels, US and European regulatory reviews, and peer-reviewed journal articles. The Css was remarkably similar to the IC50 . The median Css /IC50 value was 1.2, and 76% of the values were within 3-fold of unity. However, three drugs (encorafenib, erlotinib, and ribociclib) had a Css /IC50 value > 25. Seven other therapies targeting the same 3 kinases had much lower Css /IC50 values ranging from 0.5 to 4. These data suggest that these kinase inhibitors have a large therapeutic window that is not fully exploited; lower doses may be similarly efficacious with improved tolerability. We propose a revised first-in-human trial design in which dose cohort expansion is initiated at doses less than the MTD when there is evidence of clinical activity and Css exceeds a potency threshold. This potency-guided approach is expected to maximize the therapeutic window thereby improving patient outcomes.

Quantifying Anesthesia Exposure in Growing Rod Treatment for Early Onset Scoliosis.

BACKGROUND: Growing rod (GR) treatment for early-onset scoliosis requires repeated anesthesia exposure (AE). At a minimum, GR treatment requires AE for diagnostic imaging, index GR surgery, periodic lengthenings, and final fusion. Adjunct procedures and complication-related procedures also increase AE. To our knowledge, this is the first study to quantify AE in GR treatment and to establish preoperative expectations. METHODS: A single-center retrospective review of 16 patients who completed GR treatment and underwent final fusion. Duration of all AE related to GR treatment for "standard" care procedures (ie, advanced imaging, index surgery, lengthenings, final fusion) and "associated" care procedures (ie, revisions, adjunctive surgical procedures, wound-related complications) were reviewed. Etiologies were classified per the classification of early-onset scoliosis. Mean total anesthesia time (TAT) was tallied and analyzed for standard care and associated care procedures. RESULTS: There were 5 syndromic, 8 neuromuscular, and 3 idiopathic patients. The mean age at the first AE event related to GR treatment was 7.4 years (range, 3.8 to 11 y). Mean age at the index GR surgery and final fusion was 8.1 years (range, 3.9 to 14.4 y) and 12.8 years (range, 9.7 to 19 y), respectively. The percentage of TAT for each procedural category was 7% for advanced imaging, 14% for index GR, 14% for lengthenings, 21% for final fusion, 27% for revisions, 9% for adjunct surgery, and 9% for wound complications. Standard care procedures accounted for 55% of TAT, whereas associated care procedures accounted for 45%. CONCLUSIONS: This study quantified expected duration of AE in GR treatment. Revisions and final fusion contributed most to TAT. Given the recent controversy of repeated AE in young children, efficiency measures should be implemented to reduce AE and avoid duplication without compromising the goals of surgical treatment. Associated care procedures accounted for 45% of the total AE. LEVEL OF EVIDENCE: Level IV.

Randomized phase 2 trial of a coordinated breast cancer follow-up care program.

BACKGROUND: Previous research has demonstrated that cancer survivors often fail to receive recommended care and also undergo unnecessary care; this reduces care quality and increases costs. METHODS: This phase 2 trial randomized 100 stage 0 to IIIa breast cancer patients who had primary care providers within a large Massachusetts-based hospital network (with accessible online records) to either coordinated follow-up care (CC), which entailed a tailored survivorship care plan (SCP) and patient navigator calls every 3 months, or standard care (SC), which did not include an SCP or patient navigation, for 1 year after the completion of their last chemotherapy, surgery, or radiation treatment. The primary endpoint was the frequency of redundant examinations (>1 breast/chest wall examination per patient within any 30-day period in the absence of a new breast or chest wall complaint) over the year of follow-up. The total number of non-plastic surgery visits in the year of follow-up was a secondary endpoint. RESULTS: Two patients (both on CC) were ineligible, and 2 patients (1 per arm) had a recurrence or died during follow-up; this left 96 for analysis (47 in the CC arm and 49 in the SC arm). Twenty-two of the 47 CC patients (47%; 95% confidence interval, 32%-62%) and 19 of the 49 SC patients (39%; 95% confidence interval, 25%-54%) had 1 or more redundant breast/chest wall examinations during the year. The median number of non-plastic surgery visits was 12 for CC patients and 8 for SC patients. CONCLUSIONS: Early-stage breast cancer patients visit health care providers very frequently during their first year of follow-up and often receive unnecessary breast/chest wall examinations. An SCP and patient navigator calls did not reduce this surrogate for redundant care. Cancer 2016;122:3546-3554. © 2016 American Cancer Society.

New Minimally Invasive Technique for Direct Pars Interarticularis Osteosynthesis Using Cortical Screws and Spinous-Process Modular Link.

STUDY DESIGN: Case report. OBJECTIVE: To report a case of direct pars osteosynthesis using computed topography (CT) navigation, image guided cortically placed screws with curvilinear subspinous modular link. SUMMARY OF BACKGROUND DATA: Spondylolysis fracture is commonly encountered in athletes who subject their spines to repetitive hyperextension stress. Initial treatment is nonoperative, consisting of rest, activity modification, physical therapy, and/or bracing. When nonoperative treatment is deemed unsuccessful, surgery may be recommended. METHODS: A 17-year-old male, competitive rower, presented with 3 months of a traumatic low-back pain without radicular symptoms. After a 9-month period of nonoperative management, the patient was submitted to surgery. Using navigation, cortical screws were placed in the standard inferomedial to superolateral trajectory crossing the fracture lines. A rod was contoured in a curvilinear fashion and passed through the L4-5 interspinous ligament and connected to the screw tulip heads. RESULTS: Patient did well postoperatively and remained neurologically intact throughout his course. CT performed at 1 year demonstrated healed fracture sites without signs of fixation loosening or failure. Patient underwent removal of retained fixation approximately 16 months after surgery. Patient has returned to rowing and all sports activities with no restrictions and no reported lower back pain. CONCLUSION: This technique offers a novel solution for the treatment of pars fractures through a minimally invasive, relative muscle-sparing approach by not compromising healing potential and preserving the native facet joint. LEVEL OF EVIDENCE: 4.

Motor evoked potentials for femoral nerve protection in transpsoas lateral access surgery of the spine.

Detecting potential intraoperative injuries to the femoral nerve should be the main goal of neuromonitoring of lateral lumber interbody fusion (LLIF) procedures. We propose a theory and technique to utilize motor evoked potentials (MEPs) to protect the femoral nerve (a peripheral nerve), which is at risk in LLIF procedures. MEPs have been advocated and widely used for monitoring spinal cord function during surgical correction of spinal deformity and surgery of the cervical and thoracic spine, but have had limited acceptance for use in lumbar procedures. This is due to the theoretical possibility that MEP recordings may not be sensitive in detecting an injury to a single nerve root considering there is overlapping muscle innervation of adjacent root levels. However, in LLIF procedures, the surgeon is more likely to encounter lumbar plexus elements than nerve roots. Within the substance of the psoas muscle, the L2, L3, and L4 nerve roots combine in the lumbar plexus to form the trunk of the femoral nerve. At the point where the nerve roots become the trunk of the femoral nerve, there is no longer any alternative overlapping innervation to the quadriceps muscles. Insult to the fully formed femoral nerve, which completely blocks conduction in motor axons, should theoretically abolish all MEP responses to the quadriceps muscles. On multiple occasions over the past year, our neuro-monitoring groups have observed significantly degraded amplitudes of the femoral motor and/or sensory evoked potentials limited to only the surgical side. Most of these degraded response amplitudes rapidly returned to baseline values with a surgical intervention (i.e., prompt removal of surgical retraction).

What makes a top research medical school? A call for a new model to evaluate academic physicians and medical school performance.

Since the publication of the Flexner Report in 1910, the medical education enterprise has undergone many changes to ensure that medical schools meet a minimum standard for the curricula and clinical training they offer students. Although the efforts of the licensing and accrediting bodies have raised the quality of medical education, the educational processes that produce the physicians who provide the best patient care and conduct the best biomedical research have not been identified. Comparative analyses are powerful tools to understand the differences between institutions, but they are challenging to carry out. As a result, the analysis performed by U.S. News & World Report (USN&WR) has become the default tool to compare U.S. medical schools. Medical educators must explore more rigorous and equitable approaches to analyze and understand the performance of medical schools. In particular, a better understanding and more thorough evaluation of the most successful institutions in producing academic physicians with biomedical research careers are needed. In this Perspective, the authors present a new model to evaluate medical schools' production of academic physicians who advance medicine through basic, clinical, translational, and implementation science research. This model is based on relevant and accessible objective criteria that should replace the subjective criteria used in the current USN&WR rankings system. By fostering a national discussion about the most meaningful criteria that should be measured and reported, the authors hope to increase transparency of assessment standards and ultimately improve educational quality.

Targeting CD137 enhances the efficacy of cetuximab.

Treatment with cetuximab, an EGFR-targeting IgG1 mAb, results in beneficial, yet limited, clinical improvement for patients with head and neck (HN) cancer as well as colorectal cancer (CRC) patients with WT KRAS tumors. Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK cells contributes to the efficacy of cetuximab. The costimulatory molecule CD137 (4-1BB) is expressed following NK and memory T cell activation. We found that isolated human NK cells substantially increased expression of CD137 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. Furthermore, activation of CD137 with an agonistic mAb enhanced NK cell degranulation and cytotoxicity. In multiple murine xenograft models, including EGFR-expressing cancer cells, HN cells, and KRAS-WT and KRAS-mutant CRC, combined cetuximab and anti-CD137 mAb administration was synergistic and led to complete tumor resolution and prolonged survival, which was dependent on the presence of NK cells. In patients receiving cetuximab, the level of CD137 on circulating and intratumoral NK cells was dependent on postcetuximab time and host FcyRIIIa polymorphism. Interestingly, the increase in CD137-expressing NK cells directly correlated to an increase in EGFR-specific CD8+ T cells. These results support development of a sequential antibody approach against EGFR-expressing malignancies that first targets the tumor and then the host immune system.

Malignant osseous tumors of the pediatric spine.

In the pediatric population, malignant osseous tumors of the spine include osteosarcoma, Ewing sarcoma, lymphoma, and metastatic neuroblastoma. Although these tumors are rare, prompt diagnosis and recognition are critical to the overall prognosis. Improved understanding of the natural history of spine deformity, combined with advances in imaging, surgical technology, radiation therapy, and chemotherapeutic regimens, has improved survival rates and decreased rates of local recurrence-especially recurrence of low-grade lesions. Prognosis for patients with high-grade lesions with distant metastasis on presentation remains exceedingly poor. Recognition of these spine tumors and prompt referral to a tertiary care center that specializes in oncology can optimize patient outcomes.

Acute posttraumatic catastrophic failure of a second-generation, highly cross-linked ultra-high-molecular-weight polyethylene patellar component.

A 74-year-old man underwent total knee arthroplasty in 1996 and subsequent revision total knee arthroplasty for aseptic loosening in 2005. During revision, an all-polyethylene, 7-mm, second-generation, highly cross-linked ultra-high-molecular-weight polyethylene patellar component (Durasul; Zimmer, Warsaw, Indiana) was used. The patient recovered well, but he presented with severe acute pain after a popping feeling was detected during a game of golf in postoperative year 4. Radiographs demonstrated a fracture of the patellar component. At re-revision surgery, polyethylene fragments were encountered without visual evidence of wear. Appropriate rotational and axial alignment of the components was confirmed. Patellar revision was performed. To the authors' knowledge, this is the first report of an acute posttraumatic catastrophic fracture of a second-generation, highly cross-linked ultra-high-molecular-weight polyethylene patellar component. Although no malposition of the components was noted, abnormal tensile forces across the patellar component can be transmitted by altered patellofemoral kinematics. This combination could lead to a small surface crack that propagates deeper into the component with continued impaction and an eventual acute fracture of the entire component. The patellar component failed in a piecemeal fashion following acute trauma. Although many advantages exist to the enhancement of polyethylene patellar components, including the potential for improved wear characteristics, cross-linking has reduced resistance to crack initiation and propagation. Therefore, fracture risk should be considered when using second-generation, highly cross-linked ultra-high-molecular-weight polyethylene.

Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer.

Trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2; also known as HER-2/neu), is indicated for the treatment of women with either early stage or metastatic HER2(+) breast cancer. It kills tumor cells by several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC). Strategies that enhance the activity of ADCC effectors, including NK cells, may improve the efficacy of trastuzumab. Here, we have shown that upon encountering trastuzumab-coated, HER2-overexpressing breast cancer cells, human NK cells become activated and express the costimulatory receptor CD137. CD137 activation, which was dependent on NK cell expression of the FcγRIII receptor, occurred both in vitro and in the peripheral blood of women with HER2-expressing breast cancer after trastuzumab treatment. Stimulation of trastuzumab-activated human NK cells with an agonistic mAb specific for CD137 killed breast cancer cells (including an intrinsically trastuzumab-resistant cell line) more efficiently both in vitro and in vivo in xenotransplant models of human breast cancer, including one using a human primary breast tumor. The enhanced cytotoxicity was restricted to antibody-coated tumor cells. This sequential antibody strategy, combining a tumor-targeting antibody with a second antibody that activates the host innate immune system, may improve the therapeutic effects of antibodies against breast cancer and other HER2-expressing tumors.

Adoptive cell therapy for lymphoma with CD4 T cells depleted of CD137-expressing regulatory T cells.

Adoptive immunotherapy with antitumor T cells is a promising novel approach for the treatment of cancer. However, T-cell therapy may be limited by the cotransfer of regulatory T cells (T(reg)). Here, we explored this hypothesis by using 2 cell surface markers, CD44 and CD137, to isolate antitumor CD4 T cells while excluding T(regs). In a murine model of B-cell lymphoma, only CD137(neg)CD44(hi) CD4 T cells infiltrated tumor sites and provided protection. Conversely, the population of CD137(pos)CD44hi CD4 T cells consisted primarily of activated T(regs). Notably, this CD137(pos) T(reg) population persisted following adoptive transfer and maintained expression of FoxP3 as well as CD137. Moreover, in vitro these CD137(pos) cells suppressed the proliferation of effector cells in a contact-dependent manner, and in vivo adding the CD137(pos)CD44(hi) CD4 cells to CD137(neg)CD44(hi) CD4 cells suppressed the antitumor immune response. Thus, CD137 expression on CD4 T cells defined a population of activated T(regs) that greatly limited antitumor immune responses. Consistent with observations in the murine model, human lymphoma biopsies also contained a population of CD137(pos) CD4 T cells that were predominantly CD25(pos)FoxP3(pos) T(regs). In conclusion, our findings identify 2 surface markers that can be used to facilitate the enrichment of antitumor CD4 T cells while depleting an inhibitory T(reg) population.

Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation.

The curative potential of MHC-matched allogeneic bone marrow transplantation (BMT) is in part because of immunologic graft-versus-tumor (GvT) reactions mediated by donor T cells that recognize host minor histocompatibility antigens. Immunization with leukemia-associated antigens, such as Wilms Tumor 1 (WT1) peptides, induces a T-cell population that is tumor antigen specific. We determined whether allogeneic BMT combined with immunotherapy using WT1 peptide vaccination of donors induced more potent antitumor activity than either therapy alone. WT1 peptide vaccinations of healthy donor mice induced CD8(+) T cells that were specifically reactive to WT1-expressing FBL3 leukemia cells. We found that peptide immunization was effective as a prophylactic vaccination before tumor challenge, yet was ineffective as a therapeutic vaccination in tumor-bearing mice. BMT from vaccinated healthy MHC-matched donors, but not syngeneic donors, into recipient tumor-bearing mice was effective as a therapeutic maneuver and resulted in eradication of FBL3 leukemia. The transfer of total CD8(+) T cells from immunized donors was more effective than the transfer of WT1-tetramer(+)CD8(+) T cells and both required CD4(+) T-cell help for maximal antitumor activity. These findings show that WT1 peptide vaccination of donor mice can dramatically enhance GvT activity after MHC-matched allogeneic BMT.

Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment.

Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

Immunomodulating antibodies and drugs for the treatment of hematological malignancies.

The aim of cancer immunotherapy is to induce immune cells to kill tumor and promote immunological memory that protects against tumor recurrence. Most current immunotherapies, such as monoclonal antibodies (mAb), target the tumor cells directly. Advances in our understanding of the immune system such as the role of co-stimulatory and co-inhibitory receptors, and the advent of new immunomodulatory agents provide new opportunities to target the immune system and enhance anti-tumor immune responses. These promising agents include immunomodulating mAbs, Toll-like receptor agonists, IMiDs, and cytokines. In this review, we discuss the current results of immunomodulating agents in the treatment of hematological malignancies and propose applications that include targeting of the innate and adaptive immune systems as well as combinations with tumor-specific mAbs.

CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies.

Antibody-dependent cell-mediated cytotoxicity (ADCC), which is largely mediated by natural killer (NK) cells, is thought to play an important role in the efficacy of rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. CD137 is a costimulatory molecule expressed on a variety of immune cells after activation, including NK cells. In the present study, we show that an anti-CD137 agonistic mAb enhances the antilymphoma activity of rituximab by enhancing ADCC. Human NK cells up-regulate CD137 after encountering rituximab-coated tumor B cells, and subsequent stimulation of these NK cells with anti-CD137 mAb enhances rituximab-dependent cytotoxicity against the lymphoma cells. In a syngeneic murine lymphoma model and in a xenotransplanted human lymphoma model, sequential administration of anti-CD20 mAb followed by anti-CD137 mAb had potent antilymphoma activity in vivo. These results support a novel, sequential antibody approach against B-cell malignancies by targeting first the tumor and then the host immune system.

A CpG-loaded tumor cell vaccine induces antitumor CD4+ T cells that are effective in adoptive therapy for large and established tumors.

We designed a whole tumor cell vaccine by "loading" lymphoma tumor cells with CG-enriched oligodeoxynucleotide (CpG), a ligand for the Toll-like receptor 9 (TLR9). CpG-loaded tumor cells were phagocytosed, delivering both tumor antigen(s) and the immunostimulatory CpG molecule to antigen-presenting cells (APCs). These APCs then expressed increased levels of costimulatory molecules and induced T-cell immunity. TLR9 was required in the APCs but not in the CpG-loaded tumor cell. We demonstrate that T cells induced by this vaccine are effective in adoptive cellular therapy for lymphoma. T cells from vaccinated mice transferred into irradiated, syngeneic recipients protected against subsequent lymphoma challenge and, remarkably, led to regression of large and established tumors. This therapeutic effect could be transferred by CD4(+) but not by CD8(+) T cells. A CpG-loaded whole-cell vaccination is practical and has strong potential for translation to the clinical setting. It is currently being tested in a clinical trial of adoptive immunotherapy for mantle-cell lymphoma.