In patients with metastatic melanoma, addition of a gp100 peptide vaccine to high-dose interleukin-2 doubled response rates, delayed disease progression by a few weeks, and extended median overall ...survival by 6 months. Toxic effects were mainly those associated with high-dose interleukin-2.
Although it is clear that vaccines are important in the prevention of infectious diseases, their benefits with respect to metastatic cancer have been less clear. One of the first studies to show improved survival with vaccines among patients with metastatic cancer was reported recently in a study involving men who received sipuleucel-T vaccine for the treatment of metastatic castration-resistant prostate cancer.
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We hypothesized that the effectiveness of cancer vaccines could be improved by the simultaneous administration of specific antigens and cytokines to drive the immune response.
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Melanoma, a tumor that may be innately immunogenic in humans, is an important model . . .
We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary ...(GU) malignances.
Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).
Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.
CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid ((18)F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate ...tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging.
Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic (18)F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. (18)F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure.
(18)F FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax15-20min). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 ± 0.5 vs 2.7 ± 0.5) (P < .001); however, it was not significantly different from that of BPH (4.3 ± 0.6) (P = .27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for (18)F FACBC PET/CT and 73% and 79%, respectively, for T2-weighted MR imaging. (18)F FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined (18)F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone (P < .001).
(18)F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, (18)F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined (18)F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone.
To investigate whether apparent diffusion coefficients (ADCs) derived from diffusion-weighted (DW) magnetic resonance (MR) imaging at 3 T correlate with the clinical risk of prostate cancer in ...patients with tumors that are visible on MR images, with MR imaging/transrectal ultrasonography (US) fusion-guided biopsy as a reference.
Forty-eight consecutive patients (median age, 60 years; median serum prostate-specific antigen value, 6.3 ng/mL) who underwent DW imaging during 3-T MR imaging with an endorectal coil were included in this retrospective institutional review board-approved study, and informed consent was obtained from each patient. Patients underwent targeted MR imaging/transrectal US fusion-guided prostate biopsy. Mean ADCs of cancerous target tumors were correlated with Gleason and D'Amico clinical risk scores. The true risk group rate and predictive value of the mean ADC for classifying a tumor by its D'Amico clinical risk score was determined by using linear discriminant and receiver operating characteristic analyses.
A significant negative correlation was found between mean ADCs of tumors in the peripheral zone and their Gleason scores (P = .003; Spearman ρ = -0.60) and D'Amico clinical risk scores (P < .0001; Spearman ρ = -0.69). ADC was found to distinguish tumors in the peripheral zone with intermediate to high clinical risk from those with low clinical risk with a correct classification rate of 0.73.
There is a significant negative correlation between ADCs and Gleason and D'Amico clinical risk scores. ADCs may therefore be useful in predicting the aggressiveness of prostate cancer.
http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100667/-/DC1.
Renal cell carcinoma (RCC) clusters in some families. Familial RCC arises from mutations in several genes, including the von Hippel-Lindau (VHL) tumor suppressor, which is also mutated in sporadic ...RCC. However, a significant percentage of familial RCC remains unexplained. Recently, we discovered that the BRCA1-associated protein-1 (BAP1) gene is mutated in sporadic RCC. The BAP1 gene encodes a nuclear deubiquitinase and appears to be a classic two-hit tumor suppressor gene. Somatic BAP1 mutations are associated with high-grade, clear-cell RCC (ccRCC) and poor patient outcomes. To determine whether BAP1 predisposes to familial RCC, the BAP1 gene was sequenced in 83 unrelated probands with unexplained familial RCC. Interestingly, a novel variant (c.41T>A; p.L14H) was uncovered that cosegregated with the RCC phenotype. The p.L14H variant targets a highly conserved residue in the catalytic domain, which is frequently targeted by missense mutations. The family with the novel BAP1 variant was characterized by early-onset ccRCC, occasionally of high Fuhrman grade, and lacked other features that typify VHL syndrome. These findings suggest that BAP1 is an early-onset familial RCC predisposing gene.
BAP1 mutations may drive tumor development in a subset of patients with inherited renal cell cancer.
Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal ...cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74–99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was induced in all three patients. This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen. It also emphasizes the destructive power of small numbers of highly avid T cells and the limitations of using CEA as a target for cancer immunotherapy.
Abstract Introduction We evaluated the performance of multiparametric prostate magnetic resonance imaging (mp-MRI) and MRI/transrectal ultrasound (TRUS) fusion–guided biopsy (FB) for monitoring ...patients with prostate cancer on active surveillance (AS). Materials and methods Patients undergoing mp-MRI and FB of target lesions identified on mp-MRI between August 2007 and August 2014 were reviewed. Patients meeting AS criteria (Clinical stage T1c, Gleason grade≤6, prostate-specific antigen density≤0.15, tumor involving≤2 cores, and≤50% involvement of any single core) based on extended sextant 12-core TRUS biopsy (systematic biopsy SB) were included. They were followed with subsequent 12-core biopsy as well as mp-MRI and MRI/TRUS fusion biopsy at follow-up visits until Gleason score progression (Gleason≥7 in either 12-core or MRI/TRUS fusion biopsy). We evaluated whether progression seen on mp-MRI (defined as an increase in suspicion level, largest lesion diameter, or number of lesions) was predictive of Gleason score progression. Results Of 152 patients meeting AS criteria on initial SB (mean age of 61.4 years and mean prostate-specific antigen level of 5.26 ng/ml), 34 (22.4%) had Gleason score≥7 on confirmatory SB/FB. Of the 118 remaining patients, 58 chose AS and had at least 1 subsequent mp-MRI with SB/FB (median follow-up = 16.1 months). Gleason progression was subsequently documented in 17 (29%) of these men, in all cases to Gleason 3+4. The positive predictive value and negative predictive value of mp-MRI for Gleason progression was 53% (95% CI: 28%–77%) and 80% (95% CI: 65%–91%), respectively. The sensitivity and specificity of mp-MRI for increase in Gleason were also 53% and 80%, respectively. The number needed to biopsy to detect 1 Gleason progression was 8.74 for SB vs. 2.9 for FB. Conclusions Stable findings on mp-MRI are associated with Gleason score stability. mp-MRI appears promising as a useful aid for reducing the number of biopsies in the management of patients on AS. A prospective evaluation of mp-MRI as a screen to reduce biopsies in the follow-up of men on AS appears warranted.
CD38 overexpression was found in human lung cancer cell lines and tissues. CD38 deletion inhibited oncogenesis in vitro and in vivo. It is expected that anti-CD38 treatment may have therapeutic ...potential in lung cancer.
Abstract
The ectodomain of the plasma membrane ectoenzyme CD38 functions as both an NAD glycohydrolase and an ADP-ribosyl cyclase by catalyzing, respectively, the conversion of NAD to nicotinamide and ADP-ribose or cyclic ADP-ribose. CD38 is attracting particular attention in cancer therapy. An anti-CD38 monoclonal antibody (daratumumab) was approved for treatment of patients with multiple myeloma. However, the role of CD38 in non-hematological malignancies has not been explored. Previously, we reported that ADP-ribose-acceptor hydrolase (ARH)-1 deficiency in mice was associated with tumor development. In the present study, we found that in wild-type and ARH1-deficient mice deletion of the CD38 gene reduced tumor formation. Significant reductions in tumor number were observed in lymphomas, adenocarcinomas and hemangio/histolytic sarcomas. Consistent with a role for CD38 in tumorigenesis, CRISPR/Cas9-based knockout of CD38 in A549 human adenocarcinoma cells inhibited anchorage-independent cell growth, cell invasion and xenograft growth in nude mice. CD38 mRNA and protein expression were evaluated in human lung cancer cell lines and in human lung cancer specimens. CD38 overexpression in tumor cells was identified in 11 of 27 patient samples. In addition, some human lung cancer cell lines had dramatically higher CD38 mRNA and protein expression than normal cells. Consistent with these observations, search of the Oncomine database showed that some human lung adenocarcinomas had higher CD38 mRNA levels compared to normal lung tissues. In total, our data are consistent with the conclusion that CD38 plays a role in murine and human lung tumorigenesis and that anti-CD38 treatment may have therapeutic potential in lung cancer.
The expression and function of miR-145 in thyroid cancer is unknown. We evaluated the expression and function of miR-145 in thyroid cancer and its potential clinical application as a biomarker. We ...found that the expression of miR-145 is significantly downregulated in thyroid cancer as compared with normal. Overexpression of miR-145 in thyroid cancer cell lines resulted in: decreased cell proliferation, migration, invasion, VEGF secretion, and E-cadherin expression. miR-145 overexpression also inhibited the PI3K/Akt pathway and directly targeted AKT3. In vivo, miR-145 overexpression decreased tumor growth and metastasis in a xenograft mouse model, and VEGF secretion. miR-145 inhibition in normal primary follicular thyroid cells decreased the expression of thyroid cell differentiation markers. Analysis of indeterminate fine-needle aspiration samples showed miR-145 had a 92% negative predictive value for distinguishing benign from malignant thyroid nodules. Circulating miR-145 levels were significantly higher in patients with thyroid cancer and showed a venous gradient. Serum exosome extractions revealed that miR-145 is secreted. Our findings suggest that miR-145 is a master regulator of thyroid cancer growth, mediates its effect through the PI3K/Akt pathway, is secreted by the thyroid cancer cells, and may serve as an adjunct biomarker for thyroid cancer diagnosis.
The genetic basis for the hereditary leiomyomatosis and renal cell cancer syndrome is germ-line inactivating mutation in the
gene for the Krebs/tricarboxylic acid cycle enzyme, fumarate hydratase ...(FH), the enzyme that converts fumarate to malate.
These individuals are predisposed to development of leiomyomas of the skin and uterus as well as highly aggressive kidney
cancers. Inhibition of FH should result in significant decrease in oxidative phosphorylation necessitating that glycolysis
followed by fermentation of pyruvate to lactate will be required to provide adequate ATP as well as to regenerate NAD + . Moreover, FH deficiency is known to up-regulate expression of hypoxia-inducible factor (HIF)-1α by enhancing the stability
of HIF transcript. This leads to activation of various HIF-regulated genes including vascular endothelial growth factor and
glucose transporter GLUT1 and increased expression of several glycolytic enzymes. Because lactate dehydrogenase-A (LDH-A),
also a HIF-1α target, promotes fermentative glycolysis (conversion of pyruvate to lactate), a step essential for regenerating
NAD + , we asked whether FH-deficient cells would be exquisitely sensitive to LDH-A blockade. Here, we report that hereditary leiomyomatosis
and renal cell cancer tumors indeed overexpress LDH-A, that LDH-A inhibition results in increased apoptosis in a cell with
FH deficiency and that this effect is reactive oxygen species mediated, and that LDH-A knockdown in the background of FH knockdown
results in significant reduction in tumor growth in a xenograft mouse model. Mol Cancer Ther 2009;8(3):626–35
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