The Immune Landscape of Cancer Bortone, Dante S.; Eddy, James A.; Liu, Yuexin ...
Immunity (Cambridge, Mass.),
04/2018, Letnik:
48, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune ...subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.
Display omitted
•Six identified immune subtypes span cancer tissue types and molecular subtypes•Immune subtypes differ by somatic aberrations, microenvironment, and survival•Multiple control modalities of molecular networks affect tumor-immune interactions•These analyses serve as a resource for exploring immunogenicity across cancer types
Thorsson et al. present immunogenomics analyses of more than 10,000 tumors, identifying six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis. This work provides a resource for understanding tumor-immune interactions, with implications for identifying ways to advance research on immunotherapy.
We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically ...significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.
•Integrated analysis finds molecular features characteristic of gynecologic tumors•Subtypes with high leukocyte infiltration, a marker for immune response, identified•Gene-lncRNA interaction network of ESR1, DKC1, and lncRNAs TERC, NEAT1, and TUG1 identified•Decision tree to group patients into clinically relevant prognostic subtypes proposed
By performing molecular analyses of 2,579 TCGA gynecological (OV, UCEC, CESC, and UCS) and breast tumors, Berger et al. identify five prognostic subtypes using 16 key molecular features and propose a decision tree based on six clinically assessable features that classifies patients into the subtypes.
Abstract
BACKGROUND
Most patients with glioblastoma (GBM) receive bevacizumab as part of their treatment. There is no good therapeutic option after bevacizumab failure. Regorafenib has potent ...preclinical antitumor activity and long-lasting anti-angiogenic activity as measured by dynamic contrast enhanced (DCE) – magnetic resonance imaging (MRI). Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment.
METHODS
Patients with progression of GBM after treatment with Bevacizumab will be eligible for the study. Oral administration of Regorafenib at 160 mg once daily will be administered for 3 weeks on /1 week off. Weekly dose escalation of regorafenib from 80 mg to 160 mg/day will be employed as per the Redos strategy. Patients start the treatment 80 mg/day in week 1, with weekly dose escalation to 120 mg in week 2, then 160 mg week in 3 if no significant drug-related toxicities are observed. They will be continued on treatment with Regorafenib 160 md /day till tumor progression or toxicity. They will get MRI brain every 4 weeks during the study.
RESULTS
Primary endpoint is median Overall survival. Secondary endpoints include progression free survival at 6 months and the median time to progression and objective response rate using the modified RANO criteria. The overall safety and tolerability of regorafenib by CTCAE version 5.0. will also be reported.
CONCLUSION
This is an ongoing clinical trial.
Abstract
BACKGROUND
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its ...interaction with programmed cell death ligand 2 (PD-L2). Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. It acts in concert with the mitotic spindle apparatus to regulate cell division and localizes to the spindle microtubule organizing center (MTOC) during the G2/M phase of cell cycle progression. Survivin has also been shown to modulate the function of a number of terminal effector cell death proteases (caspases) leading to an inhibition of apoptosis.
METHODS
This is a Phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of 10 patients who have failed prior anti-PD1 therapy. The ongoing study is a phase II clinical study with a 10 patient, toxicity run-in. All patients will receive the study drug combination consisting of SurVaxM and pembrolizumab with no randomization, stratification or dose escalation.
RESULTS
So far ten patients have been enrolled on the study as safety run in. Primary endpoint is Progression free survival at 6 months. Safety and tolerability of Pembrolizumab and SurVaxM, Response rates of Pembrolizumab and SurVaxM determined using RANO criteria are secondary endpoints. Additional secondary endpoints include Overall survival and Progression Free survival Exploratory endpoints include Cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM.
CONCLUSION
This is an ongoing clinical trial.
Abstract
BACKGROUND
Glioblastoma is a devastating disease that is notoriously resistant to current therapies, leading to dismal patient outcomes and a median survival of just 14.6 months. A major ...problem in glioblastoma treatment is the inability to effectively target the cell population that gives rise to recurrence. These cells, known as glioma stem cells (GSCs) or tumor propagating cells are endowed with a large capacity for self-renewal to propagate the tumor. GSCs are resistant to radiation. Ibrutinib is a first-in-class, potent, orally administered, covalently binding Inhibitor of Bruton’s Tyrosine Kinase (BTK). Ibrutinib is a small-molecule tyrosine kinase. It also inhibits BMX. Bone marrow X-linked (BMX) nonreceptor tyrosine kinase activates STAT3 signaling to maintain self-renewal and tumorigenic potential of GSCs. Hence a combination of ibrutinib with radiation and or temozolomide in patients with newly diagnosed Glioblastoma is warranted.
METHODS
This is a two arm study. Arm 1 is for patients with unmethylated MGMT Glioblastoma. Every patient gets ibrutinib and 60 Gy radiation over 6 weeks. Patients will undergo a 4-week break and Ibrutinib treatment will then continue until disease progression, intolerable toxicity or death. Arm 2 is for patients with MGMT methylated glioblastoma. Every patient will receive Ibrutinib and 60 Gy radiation and daily Temozolomide at 75 mg/m2 for 6 weeks. Patients will undergo a 4-week break then receive daily ibrutinib and adjuvant Temozolomide. The temozolomide will continue until disease progression, intolerable toxicity or death or maximum of 6 cycles. Ibrutinib treatment will continue until disease progression, intolerable toxicity or death.
RESULTS
The maximum tolerated dose (MTD) of Ibrutinib with radiation (2 Gy x 30) in patients in each arm will be reported. The safety of Ibrutinib with radiation and with radiation and temozolomide will be reported. The Progression free survival and overall survival in each arm will be reported.
CONCLUSION
This is an ongoing clinical trial. Results will be reported once study is complete.
Abstract only
TPS2581
Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free ...survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with > 1 cm midline shift on imaging. Patients must not require > 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .
Abstract
BACKGROUND
Newly diagnosed glioblastoma (nGBM) has a dismal prognosis with survival of 15-18 months. Tumor associated “survivin” protein is expressed in >95% of nGBM and is targetable with ...the use of SurVaxM, shown to be effective at generating cytotoxic T lymphocytes.
METHODS
nGBM patients are being enrolled in this randomized placebo-controlled trial phase II study. Eligibility Criteria includes age ≥ 18, KPS ≥ 70, IHC confirmed survivin-expression, and residual contrast enhancement of ≤1 cm3 by MRI, within 72 hours of surgical resection. Patients are randomized 3:2 into two arms A:B to treatment with SurVaxM in emulsion with Montanide plus sargramostim (local injection) and standard-of-care TMZ (Arm A), or placebo (saline in emulsion with Montanide) plus saline (local injection) and standard-of-care TMZ (Arm B). There are three active treatment phases in the study with vaccine priming (VP) phase; adjuvant TMZ phase; and Vaccine Maintenance (VM) phase. A total of four (4) priming doses of SurVaxM in Montanide plus sargramostim (“SurVaxM/sargramostim”) or placebo in Montanide/saline (“Placebo/Placebo”) will be administered every two weeks ( ± 3 days) during the priming phase, with subsequent dosing every 8 weeks ( ± 1 week) during the vaccine maintenance phase. After priming doses, SurVaxM/sargramostim or Placebo/Placebo will be administered every 8 weeks ( ± 1 week) until tumor progression or for a maximum of 24 months. The total sample size is of 265 patients, with 159 patients in the SurVaxM arm and 106 patients in the control arm. The primary objective is to determine the overall survival (OS), and the secondary objectives include progression-free survival (PFS), OS at pre-specified time points (OS-15, OS-18 and OS-24), PFS at pre-specified time points (PFS-3, PFS-6 and PFS-12) and evaluation of toxicities. Study duration is expected at 36 months, with enrollment ongoing at several centers and planned for total of 20 participating centers.
Introduction
Dovitinib
is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM).
Methods
This was an open label ...phase II study of two arms: Arm 1 included anti-angiogenic naïve patients with recurrent GBM and Arm 2 included patients with recurrent GBM that had progressed on prior anti-angiogenic therapy. Nineteen subjects were enrolled in Arm 1 and 14 subjects in Arm 2. The primary endpoint was 6-month progression-free survival (PFS-6) in Arm 1 and time to progression (TTP) in Arm 2. The secondary endpoints were toxicity, objective response rate (ORR) and overall survival.
Results
Patients in Arm 2 (compared to Arm 1) tended to have longer intervals from diagnosis to study entry (median 26.9 vs. 8.9 months, p = 0.002), experienced more recurrences (64%, had 3–4 prior recurrences compared to 0, p < 0.0001) and tended to be heavily pretreated (71% vs. 26–32% p = 0.04 or 0.02). 6-month PFS was 12% ± 6% for the Arm 1 and 0% for Arm 2. TTP was similar in both treatment arms (median 1.8 months Arm 1 and 0.7–1.8 months Arm 2, p = 0.36). Five patients (15%) had grade 4 toxicities and 22 patients (67%) had grade 3 toxicities. There were no significant differences between the two arms with respect to the amount of change in the levels of biomarkers from baseline.
Conclusion
Dovitinib was not efficacious in prolonging the PFS in patients with recurrent GBM irrespective of prior treatment with anti-angiogenic therapy (including bevacizumab).
We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome ...Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily.
Display omitted
•Genetic alterations in TGF-β pathway members observed in 39% of TCGA cases•GI cancers enriched with hotspot mutations in TGF-β pathway members•Gene alterations correlated with expression of metastasis genes and poor prognosis•TGF-β signaling silenced by miRNAs or DNA methylation in hematologic cancers
To date, there are no studies of the TGF-β superfamily of signaling pathways across multiple cancers. This study represents a key starting point for unraveling the role of this complex superfamily in 33 divergent cancer types from over 9,000 patients.
PDF
