Abstract 4553: The CD25 antibody RG6292 selectively depletes Tregs while preserving IL-2 signaling and CTL activity for tumor control

2020 ◽  
Author(s):  
Maria Amann ◽  
Gabriel Schnetzler ◽  
Kolben Theresa ◽  
Isabelle Solomon ◽  
Christophe Boetsch ◽  
...  
Keyword(s):  
Tumor Control ◽  
Ctl Activity

scholarly journals Pegilodecakin, a Pegylated Human IL-10 (AM0010), Enhances the Cytotoxicity of CAR-T Cells in Vitro and In Vivo

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2058-2058 ◽  
Author(s):  
Scott McCauley ◽  
Rakesh Verma ◽  
Martin Oft
Keyword(s):  
T Cells ◽  
Clinical Outcomes ◽  
Hela Cells ◽  
Granzyme B ◽  
Tumor Control ◽  
Car T Cells ◽  
Car T ◽  
Ctl Activity

Abstract Introduction Clinical outcomes with immune cell therapies, including chimeric antigen receptor (CAR) T cells, rely on expansion of the anti-tumor T cells for successful therapeutic outcomes. Recent studies on Pegilodecakin, a pegylated interleukin-10 (IL-10), have demonstrated that doses greatly exceeding typical endogenous levels can drive a productive tumor specific T cell expansion and response. In a large Phase I/Ib study, Pegilodecakin achieved objective responses across multiple tumor types, alone and in combination with chemotherapies and immune checkpoint inhibitors, including Programmed Cell Death-1 (PD-1). Agents that improve the functional expansion of CAR-T cells, post adoptive transfer, hold promise to improve the therapeutic efficacy of the CAR-T therapies in patients. Here we report on early studies which demonstrate that Pegilodecakin significantly enhances the anti-tumor cytotoxic T lymphocyte (CTL) activity of CAR-T cells. Methods In Vitro RTCA Assays: The engineered Primary CD19 CAR-T cells were generated by isolating human T cells from whole blood and transducing these T cells with a CD19-targeted CAR. The CD19 CAR-T cells were then activated, expanded, and tested in a Real-time Cytotoxicity Assay (RTCA) against HeLa cells stably expressing human CD19 (CD19-HeLa), at multiple effector-to-target (E:T) ratios. The CTL activity or cytotoxicity was measured through cell-sensor impedance in an electronic microtiter plate. Cytotoxicity was measured for CD19 CAR-T alone or in combination with varied concentrations of Pegilodecakin, and was directly compared with controls, including Pegilodecakin alone or Pegilodecakin with non-transduced T cells. To functionally validate the CTL activity, we measured the levels of Granzyme-B and Interferon-gamma (IFNg) in the culture supernatants at the end of the RTCA by ELISA. In Vivo Raji Leukemia Model: 6-8 week old female NSG Mice NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ (NOD scid gamma), 5 mice per group, were injected with 0.5E6 Raji cells engineered to express luciferase (Raji-luc) on Day 0, IV. Tumor progression was imaged on Day 0 and weekly thereafter for 6 weeks using the Spectrum In Vivo Imaging System (IVIS). Mice were treated with varying numbers of non-transduced/CD19 CAR-T cells alone or in combination with 0.5mg/kg Pegilodecakin. Specifically, non-transduced T/CD19 CAR-T cells were administered on Days 2 and 9, with daily Pegilodecakin where indicated. Blood was collected weekly for immunophenotypic analyses. Serum was analyzed for IFNg and Granzyme B via ELISA. Results The RTCA assay revealed that Pegilodecakin in combination with the CD19 CAR-T showed a significant increase (p<0.001) in CTL activity against CD19-HeLa cells as compared to the CD19-CAR-T alone. Functionally, when combined with Pegilodecakin, CD19-CAR-T cells produced significantly higher levels of Granzyme-B (p<0.0005) and IFNg (p<0.02) in the RTCA Cytotoxicity Assay. Controls, including Pegilodecakin alone (without CAR-T or non-transduced T cells) and non-transduced T cells in combination with Pegilodecakin, had significantly lower CTL activity by RTCA or ELISA (Granzyme-B or IFNg). In the Raji-leukemia model, the Pegilodecakin combination with 5E6 CD19 CAR-T had a significant tumor control benefit by IVIS imaging, as directly compared with CD19 CAR-T monotherapy. A modest dose dependent benefit with 2.5E6 CD19 CAR-T was also observed. Conclusions We demonstrate that when combined with Pegilodecakin, the cytotoxic activity of the CD19-CAR-T is significantly improved in in vitro and in vivo models. Also, this combination demonstrates significantly improved functional activity of these CD19-CAR T cells via enhanced Granzyme-B and IFNg activity. The in vivo synergistic activity of Pegilodecakin with CD19 CAR-T demonstrates superior tumor control with potentially better depth of response. These results suggest Pegilodecakin/CAR-T therapy combination may provide longer in vivo persistence of the CAR T products offering better clinical outcomes. Disclosures McCauley: ARMO Biosciences: Employment. Verma:ARMO Biosciences: Employment. Oft:ARMO Biosciences: Employment.

404: Immune Mediated Survival Advantage and Primary Tumor Control of Cryoablation Compared to Nephrectomy in a Murine Model of Advanced Renal Cancer

2006 ◽  
Vol 175 (4S) ◽  
pp. 132-132 ◽  
Author(s):  
Sean P. Hedican ◽  
Eric R. Wilkinson ◽  
Thomas F. Warner ◽  
Fred T. Lee ◽  
Stephen Y. Nakada
Keyword(s):  
Renal Cancer ◽  
Murine Model ◽  
Primary Tumor ◽  
Survival Advantage ◽  
Tumor Control ◽  
Advanced Renal Cancer ◽  
Immune Mediated

Gamma Knife surgery combined with resection for treatment of a single brain metastasis: preliminary results

2010 ◽  
Vol 113 (Special_Supplement) ◽  
pp. 90-96 ◽  
Author(s):  
M. Yashar S. Kalani ◽  
Aristotelis S. Filippidis ◽  
Maziyar A. Kalani ◽  
Nader Sanai ◽  
David Brachman ◽  
...  
Keyword(s):  
Survival Data ◽  
Initial Treatment ◽  
Median Survival Time ◽  
Local Tumor Control ◽  
Survival Duration ◽  
Tumor Control ◽  
Local Tumor ◽  
Systemic Control ◽  
Cranial Metastasis

Object Resection and whole-brain radiation therapy (WBRT) have classically been the standard treatment for a single metastasis to the brain. The objective of this study was to evaluate the use of Gamma Knife surgery (GKS) as an alternative to WBRT in patients who had undergone resection and to evaluate patient survival and local tumor control. Methods The authors retrospectively reviewed the charts of 150 patients treated with a combination of stereotactic radiosurgery and resection of a cranial metastasis at their institution between April 1997 and September 2009. Patients who had multiple lesions or underwent both WBRT and GKS were excluded, as were patients for whom survival data beyond the initial treatment were not available. Clinical and imaging follow-up was assessed using notes from clinic visits and MR imaging studies when available. Follow-up data beyond the initial treatment and survival data were available for 68 patients. Results The study included 37 women (54.4%) and 31 men (45.6%) (mean age 60 years, range 28–89 years). In 45 patients (66.2%) there was systemic control of the primary tumor when the cranial metastasis was identified. The median duration between resection and radiosurgery was 15.5 days. The median volume of the treated cavity was 10.35 cm3 (range 0.9–45.4 cm3), and the median dose to the cavity margin was 15 Gy (range 14–30 Gy), delivered to the 50% isodose line (range 50%–76% isodose line). The patients' median preradiosurgery Karnofsky Performance Scale (KPS) score was 90 (range 40–100). During the follow-up period we identified 27 patients (39.7%) with recurrent tumor located either local or distant to the site of treatment. The median time from primary treatment of metastasis to recurrence was 10.6 months. The patients' median length of survival (interval between first treatment of cerebral metastasis and last follow-up) was 13.2 months. For the patient who died during follow-up, the median time from diagnosis of cerebral metastasis to death was 11.5 months. The median duration of survival from diagnosis of the primary cancer to last follow-up was 30.2 months. Patients with a pretreatment KPS score ≥ 90 had a median survival time of 23.2 months, and patients with a pretreatment KPS score < 90 had a median survival time of 10 months (p < 0.008). Systemic control of disease at the time of metastasis was not predictive of increased survival duration, although it did tend to improve survival. Conclusions Although the debate about the ideal form of radiation treatment after resection continues, these findings indicate that GKS combined with surgery offers comparable survival duration and local tumor control to WBRT for patients with a diagnosis of a single metastasis.

Petroclival meningiomas: long-term outcomes of multimodal treatments and management strategies based on 30 years of experience at a single institution

2020 ◽  
Vol 132 (6) ◽  
pp. 1675-1682 ◽  
Author(s):  
Jin Wook Kim ◽  
Hee-Won Jung ◽  
Yong Hwy Kim ◽  
Chul-Kee Park ◽  
Hyun-Tai Chung ◽  
...  
Keyword(s):  
Adjuvant Treatment ◽  
Management Strategies ◽  
Local Tumor Control ◽  
Tumor Control ◽  
Years Of Experience ◽  
Local Tumor ◽  
Long Term Outcomes ◽  
Single Institution ◽  
Petroclival Meningiomas

OBJECTIVEA thorough investigation of the long-term outcomes and chronological changes of multimodal treatments for petroclival meningiomas is required to establish optimal management strategies. The authors retrospectively reviewed the long-term clinical outcomes of patients with petroclival meningioma according to various treatments, including various surgical approaches, and they suggest treatment strategies based on 30 years of experience at a single institution.METHODSNinety-two patients with petroclival meningiomas were treated surgically at the authors’ institution from 1986 to 2015. Patient demographics, overall survival, local tumor control rates, and functional outcomes according to multimodal treatments, as well as chronological change in management strategies, were evaluated. The mean clinical and radiological follow-up periods were 121 months (range 1–368 months) and 105 months (range 1–348 months), respectively.RESULTSA posterior transpetrosal approach was most frequently selected and was followed in 44 patients (48%); a simple retrosigmoid approach, undertaken in 30 patients, was the second most common. The initial extent of resection and following adjuvant treatment modality were classified into 3 subgroups: gross-total resection (GTR) only in 13 patients; non-GTR treatment followed by adjuvant radiosurgery or radiation therapy (non-GTR+RS/RT) in 56 patients; and non-GTR without adjuvant treatment (non-GTR only) in 23 patients. The overall progression-free survival rate was 85.8% at 5 years and 81.2% at 10 years. Progression or recurrence rates according to each subgroup were 7.7%, 12.5%, and 30.4%, respectively.CONCLUSIONSThe authors’ preferred multimodal treatment strategy, that of planned incomplete resection and subsequent adjuvant radiosurgery, is a feasible option for the management of patients with large petroclival meningiomas, considering both local tumor control and postoperative quality of life.

Pediatric ganglioglioma of the brainstem and cervicomedullary junction: a retrospective cohort study

2020 ◽  
Vol 25 (1) ◽  
pp. 30-36
Author(s):  
Soliman Oushy ◽  
Avital Perry ◽  
Christopher S. Graffeo ◽  
Aditya Raghunathan ◽  
Lucas P. Carlstrom ◽  
...  
Keyword(s):  
Tertiary Care ◽  
Significant Risk ◽  
Foot Drop ◽  
Cranial Neuropathy ◽  
Primary Study ◽  
Tumor Control ◽  
Subtotal Resection ◽  
Low Grade ◽  
Surgical Morbidity ◽  
Cervicomedullary Junction

OBJECTIVEGanglioglioma is a low-grade central nervous system neoplasm with a pediatric predominance, accounting for 10% of all brain tumors in children. Gangliogliomas of the cervicomedullary junction (GGCMJs) and brainstem (GGBSs) present a host of management challenges, including a significant risk of surgical morbidity. At present, understanding of the prognostic factors—including BRAF V600E status—is incomplete. Here, the authors report a single-institution GGCMJ and GGBS experience and review the pertinent literature.METHODSA prospectively maintained neurosurgical database at a large tertiary care academic referral center was retrospectively queried for cases of GGCMJ pathologically confirmed in the period from 1995 to 2015; appropriate cases were defined by diagnosis codes and keywords. Secondary supplemental chart review was conducted to confirm or capture relevant data. The primary study outcome was treatment failure as defined by evidence of radiographic recurrence or progression and/or clinical or functional decline. A review of the literature was conducted as well.RESULTSFive neurosurgically managed GGBS patients were identified, and the neoplasms in 4 were classified as GGCMJ. All 5 patients were younger than 18 years old (median 15 years, range 4–16 years) and 3 (60%) were female. One patient underwent gross-total resection, 2 underwent aggressive subtotal resection (STR), and 2 underwent stereotactic biopsy only. All patients who had undergone STR or biopsy required repeat resection for tumor control or progression. Progressive disease was treated with radiotherapy in 2 patients, chemotherapy in 2, and chemoradiotherapy alone in 1. Immunostaining for BRAF V600E was positive in 3 patients (60%). All 5 patients experienced at least one major complication, including wound infection, foot drop, hemiparesis, quadriparesis, cranial neuropathy, C2–3 subluxation, syringomyelia, hydrocephalus, aspiration, and coma. Overall mortality was 20%, with 1 death observed over 11 years of follow-up.CONCLUSIONSGGBS and GGCMJ are rare, benign posterior fossa tumors that carry significant perioperative morbidity. Contemporary management strategies are heterogeneous and include combinations of resection, radiotherapy, and chemotherapy. The BRAF V600E mutation is frequently observed in GGBS and GGCMJ and appears to have both prognostic and therapeutic significance with targeted biological agents.

Adult outcome after treatment of pediatric posterior fossa ependymoma: long-term follow-up of a single consecutive institutional series of 22 patients with more than 5 years of survival

2020 ◽  
Vol 26 (1) ◽  
pp. 22-26 ◽  
Author(s):  
Tryggve Lundar ◽  
Bernt Johan Due-Tønnessen ◽  
Radek Frič ◽  
Petter Brandal ◽  
Paulina Due-Tønnessen
Keyword(s):  
Proton Beam ◽  
Posterior Fossa ◽  
Adjuvant Treatment ◽  
Tumor Control ◽  
Full Time ◽  
Time Work ◽  
Long Term Follow Up ◽  
Long Term Survivors

OBJECTIVEEpendymoma is the third most common posterior fossa tumor in children; however, there is a lack of long-term follow-up data on outcomes after surgical treatment of posterior fossa ependymoma (PFE) in pediatric patients. Therefore, the authors sought to investigate the long-term outcomes of children treated for PFE at their institution.METHODSThe authors performed a retrospective analysis of outcome data from children who underwent treatment for PFE and survived for at least 5 years.RESULTSThe authors identified 22 children (median age at the time of surgery 3 years, range 0–18 years) who underwent primary tumor resection of PFE during the period from 1945 to 2014 and who had at least 5 years of observed survival. None of these 22 patients were lost to follow-up, and they represent the long-term survivors (38%) from a total of 58 pediatric PFE patients treated. Nine (26%) of the 34 children treated during the pre-MRI era (1945–1986) were long-term survivors, while the observed 5-year survival rate in the children treated during the MRI era (1987–2014) was 13 (54%) of 24 patients. The majority of patients (n = 16) received adjuvant radiotherapy, and 4 of these received proton-beam irradiation. Six children had either no adjuvant treatment (n = 3) or only chemotherapy as adjuvant treatment (n = 3). Fourteen patients were alive at the time of this report. According to MRI findings, all of these patients were tumor free except 1 patient (age 78 years) with a known residual tumor after 65 years of event-free survival.Repeat resections for residual or recurrent tumor were performed in 9 patients, mostly for local residual disease with progressive clinical symptoms; 4 patients underwent only 1 repeated resection, whereas 5 patients each had 3 or more resections within 15 years after their initial surgery. At further follow-up, 5 of the patients who underwent a second surgery were found to be dead from the disease with or without undergoing additional resections, which were performed from 6 to 13 years after the second procedure. The other 4 patients, however, were tumor free on the latest follow-up MRI, performed from 6 to 27 years after the last resection. Hence, repeated surgery appears to increase the chance of tumor control in some patients, along with modern (proton-beam) radiotherapy. Six of 8 patients with more than 20 years of survival are in a good clinical condition, 5 of them in full-time work and 1 in part-time work.CONCLUSIONSPediatric PFE occurs mostly in young children, and there is marked risk for local recurrence among 5-year survivors even after gross-total resection and postoperative radiotherapy. Repeated resections are therefore an important part of treatment and may lead to persistent tumor control. Even though the majority of children with PFE die from their tumor disease, some patients survive for more than 50 years with excellent functional outcome and working capacity.

Stereotactic radiosurgery versus stereotactic radiotherapy for patients with vestibular schwannoma: a Leksell Gamma Knife Society 2000 debate

2000 ◽  
Vol 93 (supplement_3) ◽  
pp. 90-92 ◽  
Author(s):  
Mark E. Linskey
Keyword(s):  
Gamma Knife ◽  
Stereotactic Radiotherapy ◽  
Three Dimensional ◽  
Late Recurrence ◽  
Vestibular Schwannomas ◽  
Tumor Control ◽  
Complication Rates ◽  
Content Type ◽  
Single Fraction ◽  
Fine Print

✓ By definition, the term “radiosurgery” refers to the delivery of a therapeutic radiation dose in a single fraction, not simply the use of stereotaxy. Multiple-fraction delivery is better termed “stereotactic radiotherapy.” There are compelling radiobiological principles supporting the biological superiority of single-fraction radiation for achieving an optimal therapeutic response for the slowly proliferating, late-responding, tissue of a schwannoma. It is axiomatic that complication avoidance requires precise three-dimensional conformality between treatment and tumor volumes. This degree of conformality can only be achieved through complex multiisocenter planning. Alternative radiosurgery devices are generally limited to delivering one to four isocenters in a single treatment session. Although they can reproduce dose plans similar in conformality to early gamma knife dose plans by using a similar number of isocenters, they cannot reproduce the conformality of modern gamma knife plans based on magnetic resonance image—targeted localization and five to 30 isocenters. A disturbing trend is developing in which institutions without nongamma knife radiosurgery (GKS) centers are championing and/or shifting to hypofractionated stereotactic radiotherapy for vestibular schwannomas. This trend appears to be driven by a desire to reduce complication rates to compete with modern GKS results by using complex multiisocenter planning. Aggressive advertising and marketing from some of these centers even paradoxically suggests biological superiority of hypofractionation approaches over single-dose radiosurgery for vestibular schwannomas. At the same time these centers continue to use the term radiosurgery to describe their hypofractionated radiotherapy approach in an apparent effort to benefit from a GKS “halo effect.” It must be reemphasized that as neurosurgeons our primary duty is to achieve permanent tumor control for our patients and not to eliminate complications at the expense of potential late recurrence. The answer to minimizing complications while maintaining maximum tumor control is improved conformality of radiosurgery dose planning and not resorting to homeopathic radiosurgery doses or hypofractionation radiotherapy schemes.

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