Durable Clinical Efficacy Research Articles

204. HER2-Specific Chimeric Antigen Receptor T Cells for the Treatment of Breast-to-Brain Metastasis

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has demonstrated robust and durable clinical efficacy in patients with CD19+ B-cell malignancies. Broader application of this approach to brain and other advanced solid tumors is an immediate goal for the field and is presently under intense investigation. In 2014, 40,000 individuals in the U. S. alone succumbed to breast cancer, primarily as a result of metastatic disease. Approximately 30 percent of breast cancer patients carry an amplification of the HER2 gene and/or HER2 over-expression, which confers a particularly poor prognosis. Among the most common sites of HER2-positive breast cancer metastases is the brain. For patients with breast cancer that has metastasized to the brain, the 1-year survival rate is a dismal 20 percent. Despite clinical successes in both preventing relapse and treating systemic disease with HER2-targeted therapies, the currently available agents are only modestly effective in managing brain metastasis. Our group has demonstrated safety and transient anti-tumor responses in two U. S. FDA-authorized phase I clinical trials evaluating local intracranial adoptive transfer of CAR T cells in glioma patients.Our current project builds on this clinical experience with locally administered CAR T cells that specifically target HER2 for the treatment of breast-to-brain metastasis. Our lab has initiated design and testing of CAR T cell therapy targeting HER2 based on an scFv derived from trastuzumab. We anticipate that local intracranial delivery will enhance therapeutic response, while reducing the likelihood of off-tumor systemic toxicities as previously observed. Importantly, HER2 expression in normal brain tissue is limited, supporting HER2 as a therapeutic target in brain metastasis. Our innovative CAR T cell platform focuses on engineering central memory T cells (Tcm) for therapeutic application, with the intent of improving persistence of T cells after infusion, a critical parameter correlated with ultimate therapeutic success. Herein, we have evaluated several HER2-CAR constructs incorporating either the CD28 or 4-1BB co-stimulatory domain using both in vitro T cell functional assays as well as orthotopic patient-derived xenograft models of breast-to-brain metastasis. While HER2-28ζ and HER2-BBζ CAR T cells similarly kill HER2+ breast cancer cells in vitro, BBζ CARs demonstrate lower induction of the exhaustion marker PD-1 and proliferate better compare with 28ζ CARs. Both HER2-CARs similarly lead to tumor eradication and prolonged survival. Based on these data, we have successfully developed HER2-specific CAR T cells, and plan to clinically develop these CARs for the treatment of HER2+ metastatic disease.

Development of HER2-specific chimeric antigen receptor T cells for the treatment of breast-to-brain metastasis

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has demonstrated robust and durable clinical efficacy in patients with CD19+ B cell malignancies. Broader application of this approach to brain and other advanced solid tumors is an immediate goal for the field and is presently under intense investigation. In 2014, 40,000 individuals in the U.S. alone succumbed to breast cancer, primarily as a result of metastatic disease. Approximately 30 percent of breast cancer patients carry an amplification of the HER2 gene and/or HER2 over-expression, which confers a particularly poor prognosis. Among the most common sites of HER2-positive breast cancer metastases is the brain. For patients with breast cancer that has metastasized to the brain, the 1-year survival rate is a dismal 20 percent. Despite clinical successes in both preventing relapse and treating systemic disease with HER2-targeted therapies, the currently available agents are only modestly effective in managing brain metastasis. Our group has demonstrated safety and transient anti-tumor responses in two U.S. FDA-authorized Phase I clinical trials evaluating local intracranial adoptive transfer of CAR T cells in glioma patients. Our current project builds on this clinical experience with locally administered CAR T cells that specifically target HER2 for the treatment of breast-to-brain metastasis. Our lab has initiated design and testing of CAR T cell therapy targeting HER2 based on an scFv derived from trastuzumab. We anticipate that local intracranial delivery will enhance therapeutic response, while reducing the likelihood of off-tumor systemic toxicities as previously observed. Importantly, HER2 expression in normal brain tissue is limited, supporting HER2 as a therapeutic target in brain metastasis. Our innovative CAR T cell platform focuses on engineering central memory T cells (Tcm) for therapeutic application, with the intent of improving persistence of T cells after infusion, a critical parameter correlated with ultimate therapeutic success. Herein, we have evaluated several HER2-CAR constructs incorporating either the CD28 or 4-1BB co-stimulatory domain using both in vitro T cell functional assays as well as orthotopic patient-derived xenograft models of breast-to-brain metastasis. While HER2-28z and HER2-BBz CAR T cells similarly kill HER2+ breast cancer cells in vitro, BBz CARs demonstrate lower induction of the exhaustion marker PD-1 and proliferate better compare with 28z CARs. Both HER2-CARs similarly lead to tumor eradication and prolonged survival. Based on these data, we have successfully developed HER2-specific CAR T cells, and plan to clinically develop these CARs for the treatment of HER2+ metastatic disease.

Vascular Plug–Assisted Retrograde Transvenous Obliteration for the Treatment of Gastric Varices and Hepatic Encephalopathy: A Prospective Multicenter Study

PurposeTo evaluate technical and clinical outcomes of vascular plug–assisted retrograde transvenous obliteration (PARTO) for the treatment of gastric varices (GVs) and hepatic encephalopathy (HE). Materials and MethodsFrom March 2012 to June 2014, 73 consecutive patients (47 men, 26 women; mean age, 59 y; range, 28–79 y) who had undergone PARTO were evaluated in a prospective multicenter study. Among 57 patients with GVs, 28 had GVs in danger of rupture, 23 had experienced recent bleeding, and 6 had active variceal bleeding. The 16 patients with HE had been treated unsuccessfully with medical therapies. ResultsPlacement of the vascular plug and subsequent gelatin sponge embolization were technically successful in all 73 patients. There were no procedure-related complications. Follow-up CT obtained within 1 wk after PARTO showed complete thrombosis of GVs and portosystemic shunts in 72 of 73 patients (98.6%). Sixty patients who underwent follow-up longer than 3 mo showed complete obliteration of GVs and portosystemic shunts. There were no cases of variceal bleeding or HE at the end of follow-up (mean, 544 d). Improvement in Child–Pugh score was observed in 24 patients (40%) at 1-mo follow-up. Worsening of ascites and esophageal varices was observed in 14 (23.3%) and 16 (26.7%) patients at 3-mo follow-up. ConclusionsThe present results of PARTO indicate that it can be rapidly performed with high technical success and durable clinical efficacy for the treatment of GVs and HE in the presence of a portosystemic shunt. Therefore, PARTO might be considered a first-line treatment in appropriate patients.

Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients

Enhancing immune responses with immune-modulatory monoclonal antibodies directed to inhibitory immune receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.

Photoselective Vaporisation of the Prostate - Independent Surgical Experience Following Comprehensive Resident Training in the Technique.

Photoselective vaporisation of the prostate (PVP) is an established treatment option for bladder outlet obstruction (BOO). PVP has demonstrated durable clinical efficacy equivalent to other endoscopic procedures at 5 years [1]. Furthermore, PVP has demonstrated superior haemostatic properties compared with other endoscopic treatments for Benign Prostatic Hyperplasia (BPH) [2]. Despite this many Urological Surgeons trained in Australasia are not trained in PVP. Therefore, many urologists attempt to overcome the learning curve after a mentorship of only a handful of cases. Herein, we evaluate the first 53 cases performed independently by a single surgeon following comprehensive resident training in the technique.

Treatment of Functional Mitral Regurgitation by Percutaneous Annuloplasty Results in Durable Clinical Efficacy through 18 Months

Treatment of Functional Mitral Regurgitation by Percutaneous Annuloplasty Results in Durable Clinical Efficacy through 18 Months

Nuclear Translocation of Epidermal Growth Factor Receptor by Akt-dependent Phosphorylation Enhances Breast Cancer-resistant Protein Expression in Gefitinib-resistant Cells

Epidermal growth factor receptor (EGFR), an aberrantly overexpressed or activated receptor-tyrosine kinase in many cancers, plays a pivotal role in cancer progression and has been an attractive target for cancer therapy. Gefitinib and erlotinib, two EGFR-tyrosine kinase inhibitors, have been approved for non-small cell lung cancer. However, durable clinical efficacy of these EGFR inhibitors is severely limited by the emergence of acquired resistance. For example, the expression of breast cancer-resistant protein (BCRP/ABCG2) has been shown to confer acquired resistance of wild-type EGFR (wtEGFR)-expressing cancer cells to gefitinib. However, the underlying molecular mechanisms still remain unclear. Here, we show that wtEGFR expression is elevated in the nucleus of acquired gefitinib-resistant cancer cells. Moreover, nuclear translocation of EGFR requires phosphorylation at Ser-229 by Akt. In the nucleus, EGFR then targets the proximal promoter of BCRP/ABCG2 and thereby enhances its gene transcription. The nuclear EGFR-mediated BCRP/ABCG2 expression may contribute at least in part to the acquired resistance of wtEGFR-expressing cancer cells to gefitinib. Our findings shed light on the role of nuclear EGFR in the sensitivity of wtEGFR-expressing cancer cells to EGFR tyrosine kinase inhibitors and also deciphered a putative molecular mechanism contributing to gefitinib resistance through BCRP/ABCG2 expression.

Aortic valve re-implantation technique with Gelweave Valsalva prosthesis: safety, reproducibility and pitfalls of a geometric reconstruction

To evaluate the safety, reproducibility and pitfalls of an aortic valve re-implantation (AVRei) technique. From June 2005 to December 2008, 30 patients underwent aortic valve-sparing re-implantation with Gelweave Valsalva prosthesis. Mean age was 66 +/- 7 years (range 47-81). Mean aortic root diameter was 49 +/- 6 mm (range 37-70) and 12 patients had an aortic insufficiency more than 2+. All the patients were elective, except three who underwent surgery for type A aortic dissection. Two patients had Marfan syndrome and one had a bicuspid aortic valve. Isolated aortic root replacement was performed in 26 patients, whereas hemiarch extension was required in four. All the survivors underwent serial echocardiographic assessment for functional results and multi-detector computed tomography (MDCT) for aortic root morphology evaluation. There was one early death and one re-exploration for bleeding. Two patients suffered from a perioperative stroke and four required a pacemaker implantation because of a complete atrio-ventricular block. Mean follow-up was 12 +/- 10 months (range 1-42) with no late deaths, whereas freedom from reoperation was 100% and freedom from aortic insufficiency 2+ or more was 96.5%. MDCT aortic root reconstruction showed a pseudo-normalization of the neo-sinuses of Valsalva mimicking the human normal aortic root morphology. AVRei with Valsalva conduit is a well-tolerated procedure both in elective and emergency situations. In well-selected patients, good functional and clinical results can be achieved, regardless of the cause of the aortic root disease. Application of simple surgical manoeuvres allows durable clinical efficacy to be obtained without the risk of major complications.

The JAK Inhibitor, INCB018424, Demonstrates Durable and Marked Clinical Responses in Primary Myelofibrosis (PMF) and Post-Polycythemia/Essential Thrombocythemia Myelofibrosis (Post PV/ETMF).

Background: Myelofibrosis (MF) is characterized by progressive bone marrow dysfunction, extramedullary hematopoiesis, massive splenomegaly, elevated levels of inflammatory cytokines, severe constitutional symptoms, cachexia and premature death. INCB018424 is a potent, selective inhibitor of JAK 1 and 2 which has demonstrated impressive clinical activity in the early portion of a phase 1/2 study in patients with PMF and Post-PV/ET MF.Methods: Following the initial dose escalation phase with a BID schedule (N=11), both twice daily (10 mg BID to 25 mg BID, N=56) and once daily (25 mg QD to 200 mg QD, N= 37) dose regimens were explored. Endpoints included spleen size assessed by manual palpation, constitutional symptoms assessed using the Modified Myelofibrosis Symptom Assessment Form (MFSAF) and JAK2 allele burden. Exercise capacity is being assessed using the Six Minute Walk Test (6MWT), and body mass and composition are being assessed using standard methods. Safety was assessed by collection of adverse events and monitoring of laboratory data.Results: Over 100 patients are currently enrolled in the study, with a mean exposure to drug of > 5 months. Twenty percent of patients have received INCB018424 for > 9 months. INCB018424 is associated with a rapid reduction of splenomegaly in over 93% of patients from a mean baseline spleen size >20 cm, with 50% or greater reduction being observed in 35% of patients dosed with 10 mg BID or 50 mg QD, and 59% of patients dosed with 25mg BID regimens. These declines nearly always occur within the first month of therapy, with further, slower decreases often observed thereafter. In responding patients, spleen size reduction persists for the duration of therapy (currently up to one year follow-up). Constitutional symptoms are reported with high frequency in the study population as assessed by the MFSAF: night sweats, pruritis and fatigue were reported by >60%, >45% and >90% of patients respectively. Improvements in self-assessed symptom scores (mean % improvement of 40% to 60%) occurred by the first assessment at week 2. Activity limitations are also reported by a high proportion of MF patients; 70% of respondents reported impaired ability to exercise or get around, with a mean score >5 on the 11-point MFSAF scale; INCB018424 therapy was associated with rapid (within 2 weeks) and marked (40% or more) improvement in self-assessed score. There was a dose-dependent weight gain, most pronounced in patients with the lowest body mass index (BMI) values at baseline. Profound reductions in inflammatory cytokines were observed by the first evaluation at week 2 in virtually all patients, and were maintained during therapy. INCB018424 is generally well tolerated with the primary toxicity being dose-dependent grade 3 or 4 reversible thrombocytopenia which occurred in 0%, 18% and 32% of patients dosed with 10 mg BID, 50 mg QD or 25 mg BID.Conclusions: INCB18424 shows unprecedented and durable clinical efficacy in reducing spleen size and improving constitutional symptoms in patients with MF. Results from proactive dose modification regimens, assessments of exercise capacity, MRI-based spleen volume assessment and body composition determination will be presented.

Therapeutic Drug Monitoring of Imatinib and Impact on Clinical Decision Making.

OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making.METHODS: IM trough blood samples were collected at a time before that day's IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method.RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability.CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice.Patient IDAge, SexCML StageIM Daily Dose1st Cmin (ng/mL)Reason for Dose ChangeNew Dosing RegimenNew Cmin (ng/mL)154, fCP200 mg bid, Jan 033048, Sep 05transfusion-dependent, anemia, Sep 05300 mg, Oct 052130, Jan 0629, fCP300 mg, Jan 05not doneqRT-PCR 0.016, Jan 06400 mg, Jan 062341, Jul 06313, fCP300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 051966, Feb 06nausea, fatigue, arthralgias, myalgia, ongoing400 mg, Mar 061222, May 06467, fCP400 mg, Feb 05not donemyelosuppression, Mar 05200 mg, Mar 051928, May 06553, fCP400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04not doneinflammatory pulmonary reaction with shortness of breath; dose held, Mar 05400 mg, Oct 052378, May 06673, mCP350 mg, on phenytoin, Apr 9935, Jun 99stopped phenytoin, Jul 99500 mg, Jul 99not done; qRT-PCR negative, Jul 06CP, chronic phase1