Fungal vaccines and immunotherapeutics: current concepts and future challenges

Purpose of review The remarkable advances in modern medicine have paradoxically resulted in a rapidly expanding population of immunocompromised patients displaying extreme susceptibility to life-threatening fungal infections. There are currently no licensed vaccines, and the prophylaxis and therapy of fungal infections in at-risk individuals remains challenging, contributing to undesirable mortality and morbidity rates. The design of successful antifungal preventive approaches has been hampered by an insufficient understanding of the dynamics of the host-fungus interaction and the mechanisms that underlie heterogenous immune responses to vaccines and immunotherapy. Recent findings Recent advances in proteomics and glycomics have contributed to the identification of candidate antigens for use in subunit vaccines, novel adjuvants, and delivery systems to boost the efficacy of protective vaccination responses that are becoming available, and several targets are being exploited in immunotherapeutic approaches. Summary We review some of the emerging concepts as well as the inherent challenges to the development of fungal vaccines and immunotherapies to protect at-risk individuals.ThisworkwassupportedbytheNorthernPortugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundação para a Ciência e Tecnologia (FCT) (contracts IF/00735/ 2014 to A.C., and SFRH/BPD/96176/2013 to C.C).info:eu-repo/semantics/publishedVersio

Response to rapamycin analogs but not PD-1 inhibitors in PTEN-mutated metastatic non-small-cell lung cancer with high tumor mutational burden

Ankur R Parikh,1 Siraj M Ali,2 Alexa B Schrock,2 Lee A Albacker,2 Vincent A Miller,2 Phil J Stephens,2 Pamela Crilley,1 Maurie Markman1 1Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA; 2Foundation Medicine, Inc, Cambridge, MA, USA Abstract: In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit. Keywords: genomic profiling, temsirolimus, targeted therapy, immunotherap

Reciprocal Crosstalk between Dendritic Cells and Natural Killer T Cells: Mechanisms and Therapeutic Potential

Natural killer T cells carrying a highly conserved, semi-invariant T cell receptor (TCR) [invariant natural killer T (iNKT) cells] are a subset of unconventional T lymphocytes that recognize glycolipids presented by CD1d molecules. Although CD1d is expressed on a variety of hematopoietic and non-hematopoietic cells, dendritic cells (DCs) are key presenters of glycolipid antigen in vivo. When stimulated through their TCR, iNKT cells rapidly secrete copious amounts of cytokines and induce maturation of DCs, thereby facilitating coordinated stimulation of innate and adaptive immune responses. The bidirectional crosstalk between DCs and iNKT cells determines the functional outcome of iNKT cell-targeted responses and iNKT cell agonists are used and currently being evaluated as adjuvants to enhance the efficacy of antitumor immunotherapy. This review illustrates mechanistic underpinnings of reciprocal DCs and iNKT cell interactions and discusses how those can be harnessed for cancer therapy

Abstract P2-09-15: <i>NTRK</i> fusions in breast cancer: Clinical, pathologic and genomic findings

Abstract Background: The tropomysin receptor kinase A family includes the 3 NTRK1, NTRK2 and NTRK3 genes and plays major roles in neuronal development. The recent evidence of remarkable efficacy for kinase inhibitors (TKI) targeting NTRK across a wide variety of malignancies that harbor NTRK gene fusions has stimulated great interest in determining the type of cancers driven by these therapy defining NTRK genomic alterations. Methods: A consecutive series of 12,214 locally aggressive, relapsed and metastatic breast malignancies (mBM) were subjected to comprehensive genomic profiling (CGP) using DNA extracted from 40 µm of FFPE sections and adaptor ligation-based libraries to a mean coverage depth 719X for up to 315 cancer-related genes. The results were analyzed for all classes of genomic alterations (GA) including base substitutions, insertions and deletions, select fusions and rearrangements, and copy number changes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA. Microsatellite instability (MSI) status was calculated by a customized algorithm. Results: 16 (0.13%) mBM (all female) harbored NTRK gene fusions. The median age was 51 years (range 34 to 70 years). There were 9 ductal carcinomas, 2 lobular carcinomas, 3 secretory carcinomas 1 metaplastic carcinoma and 1 angiosarcoma. Tumor stages at the time of sequencing were 12 Stage IV, 1 Stage III and 3 stage I (all 3 secretory carcinomas). In 9 cases, clinical receptor status was known: 3 (33%) were ER+/HER2- and 6 (66%) ER-/HER2- (all TNBC) with all 9 (100%) of cases HER2-. All 3 SCA were TNBC. 10 NTRK fusions involved NTRK1 featuring a variety of fusion partners (CGN, GATAD2B, LMNA, MDM4, PEAR1, and TPM3) and 6 involved NTRK3 (all ETV6 fusions). There were no NTRK2 fusions. NTRK fusion+ mBM featured a mean of 4.25 GA per sample. The most frequent non-fusion partner co-altered genes in this series of NTRK fusion+ mBM were: TP53 at 25%, IKBKE, PIK3C2B CCND1 at 19%, and AKT, PIK3CA, MYC, CDH1, CDKN2A, PTEN, FGF3, FGF4 and FGF19 all at 13%. The median TMB for NTRK fusion+ mBM was 0.9 mutations/Mb and no cases (0%) had a TMB &amp;gt; 10 mutations/Mb and no cases (0%) feared high microsatellite instability (MSI high). Clinical response assessment to NTRK TKI therapies in this series is ongoing. Conclusions: NTRK gene fusions although extremely uncommon in breast malignancies occur across a variety of tumor types, is universally HER2 negative, more frequent in TNBC than in ER+ tumors, is associated with a moderate frequency of additional genomic alterations and a complete absence of either high TMB or high MSI. This study confirms that a CGP assay, when applied to a large cohort of near universal clinically advanced disease can identify extremely rare alterations that can lead a small number of patients to highly effective precision therapies. Citation Format: Ross JS, Chung J, Elvin JE, Vergilio J-A, Ramkissoon S, Suh J, Severson E, Daniel S, Frampton GM, Fabrizio D, Hartmaier RJ, Albacker LA, Ali SM, Schrock AB, Miller VA, Stephens PJ, Gay LM. NTRK fusions in breast cancer: Clinical, pathologic and genomic findings [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-15.</jats:p

Abstract PD8-01: <i>CDH1</i> mutated classic and pleomorphic invasive lobular breast carcinomas differ in genomic signatures and opportunities for targeted and immunotherapies

Abstract Background: Typically defined by negative IHC staining for E-cadherin, classic (CILC) and pleomorphic (PILC) are often combined as a single breast cancer subtype. We queried whether patients with relapsed metastatic disease, mCILC and mPILC, would harbor contrasting genomic alterations (GA)and that molecular information could further differentiate the 2 tumor types and thereby influence therapy selection. Methods: DNA was extracted from 40 µm of FFPE sections of 10,784 invasive breast carcinomas. 454 (4%) CDH1 mutated mILC were selected including 428 classic mCILC (94%) and 26 mPLIC (6%) subtypes. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth &amp;gt;600X for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA. Results: mCILC and mPILC patients featured a median age of 63 years (Table). Slide based ER+ status and HER2+ status was significantly different in both groups (P&amp;lt;0.0001). The frequency of base substitutions in ESR1 was significantly higher in mCILC, and this difference was also significantly higher in mCILC metastasis biopsies exposed to hormonal therapy than in pre-treatment primary tumors (P&amp;lt;0.0001). ERBB2 (HER2) GA (amp + non-amp) detected by CGP were higher in mPILC than mCILC in both pre-and post-treatment samples (P&amp;lt;0.0001 for both). The ERBB2 GA frequency was nearly twice as high after hormonal therapy in both mCILC and mPILC. ESR1 and ERBB2 GA were mutually exclusive overall and especially in the mCILC group. PIK3CA GA were the most frequent GA in both mCILC and mPILC. TP53 GA were significantly more frequent in mPILC than mCILC. At 19%, the frequency of TMB &amp;gt; 15 mutations/MB in mPILC was more than twice as frequent than in mCILC (P=0.046). All (100%) of both the CILC and PILC groups were negative for mis-match repair deficiency or MSI high status. mCILC and mPILC patients with post primary therapy associated ESR1 and ERBB2 GA responding to targeted and immunotherapies will be presented. Contrasting Clinical and Genomic Features of CILC and PILC Classic CILC (428 cases)Pleomorphic PILC (26 cases)Median Age6363*ER+98%74%*HER2 IHC/FISH+12 (3%)6 (22%)ESR1 GA Primary Pre-Rx6%0%ESR1 GA Metastatic Post-Rx17%0%ERBB2 GA Primary Pre-Rx7%18%ERBB2 GA Metastatic Post-Rx12%34%Other Significant GAPIK3CA (55%), CCND1 (21%), TP53 (17%), ARID1A, AKT3, MDM4, PTEN (all 11%)PIK3CA (58%), TP53 (30%), AKT1 22%), FGFR4, CCND1, PTEN (all 17%)TMB median (mut/Mb)2.73.6TMB &amp;gt; 15%8%19%*when clinical status available Conclusions: CGP of mCILC and mPILC reveals significant differences in the panorama of GA both in pre-treatment primary and metastatic disease lesions especially in therapy-impacting GA in ESR1 and ERBB2. mCILC is more often driven by ESR1 GA and mPILC by ERBB2 GA. Although both mCILC and mPILC feature subsets of tumors with high TMB, this is more frequent for mPILC likely indicating different potentials for immunotherapies to benefit these patients. Citation Format: Ross JS, Chung J, Elvin JE, Vergilio J-A, Ramkissoon S, Suh J, Severson E, Daniel S, Frampton GM, Fabrizio D, Hartmaier RJ, Albacker LA, Ali SM, Schrock AB, Miller VA, Stephens PJ, Gay LM. CDH1 mutated classic and pleomorphic invasive lobular breast carcinomas differ in genomic signatures and opportunities for targeted and immunotherapies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-01.</jats:p

TIM-4, expressed by medullary macrophages, regulates respiratory tolerance by mediating phagocytosis of antigen-specific T cells

Respiratory exposure to antigen induces T cell tolerance via several overlapping mechanisms that limit the immune response. While the mechanisms involved in the development of Treg cells have received much attention, those that result in T cell deletion are largely unknown. Herein, we show that F4/80(+) lymph node medullary macrophages expressing TIM-4, a phosphatidylserine receptor, remove antigen-specific T cells during respiratory tolerance, thereby reducing secondary T cell responses. Blockade of TIM-4 inhibited the phagocytosis of antigen-specific T cells by TIM-4 expressing lymph node medullary macrophages, resulting in an increase in the number of antigen-specific T cells and the abrogation of respiratory tolerance. Moreover, specific depletion of medullary macrophages inhibited the induction of respiratory tolerance, highlighting the key role of TIM-4 and medullary macrophages in tolerance. Therefore, TIM-4-mediated clearance of antigen specific T cells represents an important previously unrecognized mechanism regulating respiratory tolerance

Covalent ERα Antagonist H3B-6545 Demonstrates Encouraging Preclinical Activity in Therapy-Resistant for Breast Cancer

UNLABELLED: Nearly 30% of patients with relapsed breast cancer present activating mutations in estrogen receptor alpha (ERα) that confer partial resistance to existing endocrine-based therapies. We previously reported the development of H3B-5942, a covalent ERα antagonist that engages cysteine-530 (C530) to achieve potency against both wild-type (ERαWT) and mutant ERα (ERαMUT). Anticipating that the emergence of C530 mutations could promote resistance to H3B-5942, we applied structure-based drug design to improve the potency of the core scaffold to further enhance the antagonistic activity in addition to covalent engagement. This effort led to the development of the clinical candidate H3B-6545, a covalent antagonist that is potent against both  ERαWT/MUT, and maintains potency even in the context of ERα C530 mutations. H3B-6545 demonstrates significant activity and superiority over standard-of-care fulvestrant across a panel of ERαWT and ERαMUT palbociclib sensitive and resistant models. In summary, the compelling preclinical activity of H3B-6545 supports its further development for the potential treatment of endocrine therapy-resistant ERα+ breast cancer harboring wild-type or mutant ESR1, as demonstrated by the ongoing clinical trials (NCT03250676, NCT04568902, NCT04288089). SUMMARY: H3B-6545 is an ERα covalent antagonist that exhibits encouraging preclinical activity against CDK4/6i naïve and resistant ERαWT and ERαMUT tumors