Personal neoantigen vaccines have been envisioned as an effective approach to induce, amplify and diversify antitumor T cell responses. To define the long-term effects of such a vaccine, we evaluated ...the clinical outcome and circulating immune responses of eight patients with surgically resected stage IIIB/C or IVM1a/b melanoma, at a median of almost 4 years after treatment with NeoVax, a long-peptide vaccine targeting up to 20 personal neoantigens per patient ( NCT01970358 ). All patients were alive and six were without evidence of active disease. We observed long-term persistence of neoantigen-specific T cell responses following vaccination, with ex vivo detection of neoantigen-specific T cells exhibiting a memory phenotype. We also found diversification of neoantigen-specific T cell clones over time, with emergence of multiple T cell receptor clonotypes exhibiting distinct functional avidities. Furthermore, we detected evidence of tumor infiltration by neoantigen-specific T cell clones after vaccination and epitope spreading, suggesting on-target vaccine-induced tumor cell killing. Personal neoantigen peptide vaccines thus induce T cell responses that persist over years and broaden the spectrum of tumor-specific cytotoxicity in patients with melanoma.
ATP-competitive fibroblast growth factor receptor (FGFR) kinase inhibitors, including BGJ398 and Debio 1347, show antitumor activity in patients with intrahepatic cholangiocarcinoma (ICC) harboring ...activating
gene fusions. Unfortunately, acquired resistance develops and is often associated with the emergence of secondary
kinase domain mutations. Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with
2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347. Examination of serial biopsies, circulating tumor DNA (ctDNA), and patient-derived ICC cells revealed that TAS-120 was active against multiple FGFR2 mutations conferring resistance to BGJ398 or Debio 1347. Functional assessment and modeling the clonal outgrowth of individual resistance mutations from polyclonal cell pools mirrored the resistance profiles observed clinically for each inhibitor. Our findings suggest that strategic sequencing of FGFR inhibitors, guided by serial biopsy and ctDNA analysis, may prolong the duration of benefit from FGFR inhibition in patients with
fusion-positive ICC. SIGNIFICANCE: ATP-competitive FGFR inhibitors (BGJ398, Debio 1347) show efficacy in
-altered ICC; however, acquired
kinase domain mutations cause drug resistance and tumor progression. We demonstrate that the irreversible FGFR inhibitor TAS-120 provides clinical benefit in patients with resistance to BGJ398 or Debio 1347 and overcomes several FGFR2 mutations in ICC models.
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Abstract
The inevitable emergence of acquired resistance is a major limitation to the clinical benefit of precision medicine strategies. Single-lesion tumor biopsies have long been the mainstay of ...understanding acquired resistance, but recent data suggest tumor biopsies may under-represent the molecular heterogeneity of acquired resistance. Alternatively, studies have suggested that liquid biopsy approaches analyzing cell-free DNA (cfDNA) may offer significant advantages, but extensive prospective comparisons of matched liquid vs. tumor biopsies obtained at the time of acquired resistance are lacking. Here, we assess systematic liquid biopsy upon acquired resistance to targeted therapy in 44 patients across seven molecularly defined subtypes of gastrointestinal cancers. Liquid biopsy at disease progression identified at least one functionally validated molecular mechanism of resistance in 75% of patients, wherein 52% exhibited >1 resistance alteration (range 2-9, median 3 per patient). In 23 patients in whom a matched post-progression tumor biopsy could be obtained, tumor biopsy was less effective than liquid biopsy in identifying resistance mechanisms, with resistance alterations detected in only 48% of patients, and multiple resistance mechanisms detected in only 9% of cases. In matched cases, liquid biopsy detected at least one resistance alteration not detected in tumor biopsy in 78% of cases. Targeted analysis and whole-exome sequencing of serial cfDNA, multiple post-progression biopsies, and rapid autopsy specimens from select cases revealed key insights into the geographic and complex characteristics of heterogeneity captured by liquid biopsy in the setting of acquired resistance. These data illustrate that acquired resistance is characterized by frequent and profound tumor heterogeneity, and suggests that liquid biopsy may more effectively identify heterogeneous clinically relevant resistance alterations compared to standard tumor biopsy.
Citation Format: Aparna R. Parikh, Ignaty Leshchiner, Liudmila Elagina, Lipika Goyal, Chaya Levovitz, Giulia Siravegna, Dimitri Livitz, Kahn Rhrissorrakrai, Liz Martin, Emily E. Van Seventer, Megan Hanna, Kara Slowik, Filippo Utro, Christopher J. Pinto, Alicia Wong, Brian P. Danysh, Ferran Fece de la Cruz, Isobel J. Fetter, Brandon Nadres, Heather A. Shahzade, Jill N. Allen, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Bruce Giantonio, Janet E. Murphy, Ryan D. Nipp, Eric Roeland, David P. Ryan, Colin D. Weekes, Eunice L. Kwak, Jason E. Faris, Francois Aguet, Ipsita Guha, Mehlika Hazar-Rethinam, Dora Dias-Santagata, David T. Ting, Andrew X. Zhu, Theodore S. Hong, Todd R. Golub, A J. Iafrate, Viktor Adalsteinsson, Alberto Bardelli, Laxmi Parida, Dejan Juric, Gad Getz, Ryan B. Corcoran. Liquid biopsy versus tissue biopsy to assess acquired resistance and tumor heterogeneity in gastrointestinal cancers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-257.
Whereas the quality of the program depends on promptness, full coverage, vaccination schedule abidance. Taking new Moscow regions as an example there have been studied factors influencing vaccination ...against Pneumococcal infection (PI). Insufficient provision of the vaccine to reach the desired level of coverage has been detected: in 2014 only 67.57% of liable children could receive double vaccination; the available quantity of vaccine in 2015 was able to provide 33. 84% of children up to 12 months old with double vaccination.However, the actual number of children vaccinated turned to be much lower (0.23% in 2014 and 20.85% in 2015).The survey of the doctors with the purpose of defining the level of knowledge and commitment to the vaccination against PI has shown a modest level of epidemiology, clinical implications, PIimmunoprophylaxis method awareness. Parental attitude towards PI vaccination has been estimated as positive. Parental interest to opportunities of immunoprophylaxis against PI is worthwhile noting despite the insufficient level of knowledgeability of its effects. Hence 74.5% of parents whose children are not vaccinated against PI would like to start vaccination, however a part of them look into receiving more information (29.41% parents).
Clinical and bacteriological studies have revealed that the production of colicin by Escherichia coli forming a part of intestinal microbiocenosis is related to the clinical manifestations of ...inflammatory diseases of the gastrointestinal tract. During the exacerbation of chronic inflammatory processes of the digestive system the proportion of colicin producing E. coli increases (more than 45%) in comparison with that of E. coli fecal strains isolated in children and adolescents regarded as healthy (less than 15%). The possibility of using the colicin producing activity of intestinal microflora for the evaluation of the dysbiotic states of gastrointestinal tract is discussed.
The specific features of intestinal aerobic and anaerobic intestinal microflora in children with nondifferentiated connective tissue dysplasia were under study. A high rate of dysbiotic disturbances ...was noted in patients with connective tissue dysplasia in comparison with healthy persons. Profound quantitative and qualitative changes in the biocenosis of the intestine were detected in patients with the pathology of the gastrointestinal tract as well as that of the locomotor system. Changes in the species composition and the persistence properties of the intestinal microflora may serve as pathogenetic factors in the development of connective tissue dysplasia.
The influence of the exometabolites of the fungus S. boulardii, contained in the probiotic preparation "Enterol", on the biological properties of opportunistic and pathogenic enterobacteria of fecal ...microflora (inactivation of lysozyme, colicin production, hemolytic activity, antibiotic resistance) was studied. The study revealed that the supernatants of S. boulardii decreased antilysozyme activity (ALA) in lactose positive (lac+) and lactose negative (lac-) Escherichia coli and Klebsiella strains, but produced no influence on ALA in Salmonella. In response to the action of S. boulardii exometabolites colicin production in E. coli (lac+) was found to increase, while in E. coli (lac-) colicin production was suppressed. An increase in the sensitivity of lactose negative E. coli to cefazolin and cefotaxime under the action of S. boulardii supenatants was noted. The results obtained in this study show the probable mechanism of the corrective action of "Enterol" on intestinal biocenosis, which should be taken into consideration in the differentiated selection of probiotics for the treatment of intestinal dysbacteriosis.
To evaluate effectiveness of sulodexide in patients with pyonecrotic complications of diabetic foot.
Sulodexide was given to 15 patients which were examined for blood fibrinogen, foot tissues ...saturation with oxygen, microbic contamination of the wound tissue. In addition, ultrasound dopplerography of foot arteries, laser doppler flowmetry were performed.
Fibrinogen in peripheral blood fell, arteriovenous shunting diminished, capillary blood flow and oxygen saturation of the tissues improved.
Even early sulodexide treatment is effective at different stages of the pathological process in diabetic patients with severe pyonecrotic lesion of the lower limbs as it recovers microcirculatory blood flow.
For the period from 1996 to 1998 in the Division of wounds and wound infection of A.V. Vishnevsky Institute of Surgery 92 patients with pyonecrotic forms of "diabetic foot" underwent thorough ...examination and treatment. The patients were divided into groups by the form of "diabetic foot": with pyonecrotic forms of "diabetic foot" without critical ischemia (group 1) and with it (group 2). In 18 patients of both groups the data of electron autoradiography were used to reveal peculiarities of the wound process. Group 1 patients had at admittance a large number of neutrophiles in various stages of destruction in biopsies of the wound. In patients of group 2 a great majority of the vessels in biopsies of the wound were in different stages of destruction with lost connections between their separate cells or some of their part absent. Separate cells (endotheliocytes and pericytes) which make up the walls of destroying vessels, were synthesizing RNA and were functionally active. In both groups, the studied parts of the wound before plastic repair of its defect usually represented as well developed granulation tissues with a number of microvessels and cells. Intensive synthesis of PNA in the cells of microvascular wall evidenced of their high functional activity, and the synthesis of DNA in them showed their ability for proliferation, i.g.--for growth. Thus, microangiopathy was reversible, and the solution of the problem of critical ischemia should be considered in the light of macroangiopathy. Thus, in patients of group 1 the cause of pyonecrotic damage consists in infection process, while in patients of group 2--in combination of infection with ischemia of the extremity. In both groups pyonecrotic disease of the extremity ruses at the background of severe disturbances of cellular immunity.
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