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Targeted protein degradation (TPD) has emerged as a prominent and vital strategy for therapeutic intervention of cancers and other diseases. One such approach involves the exploration of proteolysis targeting chimeras (PROTACs) for the selective elimination of disease-causing proteins through the innate ubiquitin-proteasome pathway. Due to the unprecedented achievements of various PROTAC molecules in clinical trials, researchers have moved towards other physiological protein degradation approaches for the targeted degradation of abnormal proteins, including lysosome-targeting chimeras (LYTACs), autophagy-targeting chimeras (AUTACs), autophagosome-tethering compounds (ATTECs), molecular glue degraders, and other derivatives for their precise mode of action. Despite numerous advantages, these molecules face challenges in solubility, permeability, bioavailability, and potential off-target or on-target off-tissue effects. Thus, an urgent need arises to direct the action of these degrader molecules specifically against cancer cells, leaving the proteins of non-cancerous cells intact. Recent advancements in TPD have led to innovative delivery methods that ensure the degraders are delivered in a cell- or tissue-specific manner to achieve cell/tissue-selective degradation of target proteins. Such receptor-specific active delivery or nano-based passive delivery of the PROTACs could be achieved by conjugating them with targeting ligands (antibodies, aptamers, peptides, or small molecule ligands) or nano-based carriers. These techniques help to achieve precise delivery of PROTAC payloads to the target sites. Notably, the successful entry of a Degrader Antibody Conjugate (DAC), ORM-5029, into a phase 1 clinical trial underscores the therapeutic potential of these conjugates, including LYTAC-antibody conjugates (LACs) and aptamer-based targeted protein degraders. Further, using bispecific antibody-based degraders (AbTACs) and delivering the PROTAC pre-fused with E3 ligases provides a solution for cell type-specific protein degradation. Here, we highlighted the current advancements and challenges associated with developing new tumour-specific protein degrader approaches and summarized their potential as single agents or combination therapeutics for cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Antibody-drug conjugates (ADCs) have high specificity with lesser off-target effects, thus providing improved efficacy over traditional chemotherapies. A total of 14 ADCs have been approved for use against cancer by the US Food and Drug Administration (FDA), with more than 100 ADCs currently in clinical trials. Of particular interest ADCs targeting immune antigens PD-L1, B7-H3, B7-H4 and integrins. Specifically, we describe ADCs in development along with the gene and protein expression of these immune checkpoints across a wide range of cancer types let url = window.clickTag || window.clickTag1 || window.clickTag2 || window.clickTag3 || window.clickTag4 || window.bsClickTAG || window.bsClickTAG1 || window.bsClickTAG2 || window.url || ''; if(typeof url == 'string'){ document.body.dataset['perxceptAdRedirectUrl'] = url;}., Competing Interests: Declaration of Competing Interest AR has received advisory board honoraria from AstraZeneca, Merck Sharp & Dohme, Novartis, and Pfizer; writing engagement honoraria from AstraZeneca, Merck Sharp & Dohme, and Novartis; and speaker bureau from Bristol-Myers Squibb. UM has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, Janssen, Diatech, Novartis, and Hedera., for work performed outside of the current study. AD has consulting/advisory role for Sanofi, Amgen, Foundation Medicine, AstraZeneca, Janssen Oncology, Merus, Daichii Sankyo, Abbvie, Regeneron, Bristol Myers Squibb, Bayer. AD has recieved research funding from Lung Cancer Research Foundation, LUNGevity Foundation., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53 -/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53 -/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis., Competing Interests: Declaration of interests A.A.S. has served as a consultant for Boehringer Ingelheim and Pharmacosmos and is a former employee of Tempus Labs. C.J.K. is a scientific advisory board member for Surrozen, Inc., Mozart Therapeutics, and NextVivo. C.C. has served as a scientific advisory board member/consultant for Genentech, Grail, DeepCell, Nanostring, and Viosera. W.C.H. is a consultant for Thermo Fisher, Solasta Ventures, MPM Capital, KSQ Therapeutics, Tyra Biosciences, Frontier Medicine, Jubilant Therapeutics, RAPPTA Therapeutics, Hexagon Bio, Serinus Biosciences, Function Oncology, and Calyx., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Despite the recent influx of immunotherapies and small molecule drugs to treat tumors, cancer remains a leading cause of death in the United States, in large part due to the difficulties of treating metastatic cancer. Stem cells, which are inherently tumoritropic, provide a useful drug delivery vehicle to target both primary and metastatic tumors. Intravenous infusions of stem cells carrying or secreting therapeutic payloads show significant promise in the treatment of cancer. Stem cells may be engineered to secrete cytotoxic products, loaded with oncolytic viruses or nanoparticles containing small molecule drugs, or conjugated with immunotherapies. Herein we describe these preclinical and clinical studies, discuss the distribution and migration of stem cells following intravenous infusion, and examine both the limitations of and the methods to improve the migration and therapeutic efficacy of tumoritropic, therapeutic stem cells., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although there are exceptions and outliers, T cell functional responses generally correlate with the affinity of a TCR for a peptide/MHC complex. In one recently described outlier case, the most promising clinical candidate in a series of TCRs specific for the gp100 209 melanoma antigen bound with the weakest solution affinity and produced the least amount of cytokine in vitro. Hypotheses for this outlier behavior included unusual cytokine expression patterns arising from an atypical TCR binding geometry. Studying this instance in more detail, we found here that outlier behavior is attributable not to unusual cytokine patterns or TCR binding, but the use of a position 2 anchor-modified peptide variant in in vitro experiments instead of the wild type antigen that is present in vivo. Although the anchor-modified variant has been widely used in basic and clinical immunology as a surrogate for the wild type peptide, prior work has shown that TCRs can clearly distinguish between the two. We show that when this differential recognition is accounted for, the functional properties of gp100 209 -specific TCRs track with their affinity towards the peptide/MHC complex. Beyond demonstrating the correlates with T cell function for a clinically relevant TCR, our results provide important considerations for selection of TCRs for immunotherapy and the use of modified peptides in immunology., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

CD8+ T cell recognition of peptide epitopes plays a central role in immune responses against pathogens and tumors. However, the rules that govern which peptides are truly recognized by existing T cell receptors (TCRs) remain poorly understood, precluding accurate predictions of neo-epitopes for cancer immunotherapy. Here, we capitalize on recent (neo-)epitope data to train a predictor of immunogenic epitopes (PRIME), which captures molecular properties of both antigen presentation and TCR recognition. PRIME not only improves prioritization of neo-epitopes but also correlates with T cell potency and unravels biophysical determinants of TCR recognition that we experimentally validate. Analysis of cancer genomics data reveals that recurrent mutations tend to be less frequent in patients where they are predicted to be immunogenic, providing further evidence for immunoediting in human cancer. PRIME will facilitate identification of pathogen epitopes in infectious diseases and neo-epitopes in cancer immunotherapy., Competing Interests: The authors declare no competing interests. G. Ciriello is a member of the advisory board of Cell Reports Medicine., (© 2021 The Author(s).)

The development of immunological therapies that incorporate peptide antigens presented to T cells by MHC proteins is a long sought-after goal, particularly for cancer, where mutated neoantigens are being explored as personalized cancer vaccines. Although neoantigens can be identified through sequencing, bioinformatics and mass spectrometry, identifying those which are immunogenic and able to promote tumor rejection remains a significant challenge. Here we examined the potential of high-resolution structural modeling followed by energetic scoring of structural features for predicting neoantigen immunogenicity. After developing a strategy to rapidly and accurately model nonameric peptides bound to the common class I MHC protein HLA-A2, we trained a neural network on structural features that influence T cell receptor (TCR) and peptide binding energies. The resulting structurally-parameterized neural network outperformed methods that do not incorporate explicit structural or energetic properties in predicting CD8 + T cell responses of HLA-A2 presented nonameric peptides, while also providing insight into the underlying structural and biophysical mechanisms governing immunogenicity. Our proof-of-concept study demonstrates the potential for structure-based immunogenicity predictions in the development of personalized peptide-based vaccines.

Objective: To assess the trends of inpatient resource use and mortality in pediatric hospitalizations for fever with neutropenia in the US from 2007 to 2014., Study Design: Using National (Nationwide) Inpatient Sample (NIS) and International Classification of Diseases, Ninth Revision, Clinical Modification codes, we studied pediatric cancer hospitalizations with fever with neutropenia between 2007 and 2014. Using appropriate weights for each NIS discharge, we created national estimates of median cost, length of stay, and in-hospital mortality rates., Results: Between 2007 and 2014, there were 104 315 hospitalizations for pediatric fever with neutropenia. The number of weighted fever with neutropenia hospitalizations increased from 12.9 (2007) to 18.1 (2014) per 100 000 US population. A significant increase in fever with neutropenia hospitalizations trend was seen in the 5- to 14-year age group, male sex, all races, and in Midwest and Western US hospital regions. Overall mortality rate remained low at 0.75%, and the 15- to 19-year age group was at significantly greater risk of mortality (OR 2.23, 95% CI 1.36-3.68, P = .002). Sepsis, pneumonia, meningitis, and mycosis were the comorbidities with greater risk of mortality during fever with neutropenia hospitalizations. Median length of stay (2007: 4 days, 2014: 5 days, P < .001) and cost of hospitalization (2007: $8771, 2014: $11 202, P < .001) also significantly increased during the study period., Conclusions: Our study provides information regarding inpatient use associated with fever with neutropenia in pediatric hospitalizations. Continued research is needed to develop standardized risk stratification and cost-effective treatment strategies for fever with neutropenia hospitalizations considering increasing costs reported in our study. Future studies also are needed to address the greater observed mortality in adolescents with cancer., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Iron overload is a significant cause of morbidity and mortality for patients who require frequent transfusions. We completed a prospective, cross-sectional study to evaluate the prevalence of iron overload in previously transfused childhood cancer survivors. Survivors recruited from the University of Minnesota Long-Term Follow-Up Clinic were stratified into 3 groups: oncology patients not treated with hematopoietic stem cell transplantation (HSCT) (n=27), patients treated with allogeneic HSCT (n=27), and patients treated with autologous HSCT (n=9). Serum ferritin was collected and hepatic magnetic resonance imaging (FerriScan) was obtained for those with iron overload (defined as ferritin ≥1000 ng/mL). The prevalence of iron overload in subjects with a history of allogeneic HSCT was 25.9% (95% CI, 9.4%-42.5%) compared with only 3.7% (95% CI, 0%-10.8%) in subjects treated without HSCT and 0% in subjects treated with autologous HSCT. No association was found between serum ferritin levels and the presence of cardiac, liver, or endocrine dysfunction. The prevalence of iron overload in subjects who received no HSCT or autologous HSCT is low in our study. A higher prevalence was found in patients receiving allogeneic HSCT, reiterating the importance of screening these patients for iron overload in accordance with the current Children's Oncology Group Long Term Follow-Up Guidelines.

Clinical studies have been initiated in conformal radiotherapy using a computer controlled multi-leaf collimator. Quantitative dosimetry and treatment planning studies comparing field shaping by lead alloy blocks and the multi-leaf collimator demonstrate the clinical acceptability of the multi-leaf collimator. Sixteen patients with tumors in multiple sites have received some part of their treatments with both blocking systems. Studies of dosimetry and field shaping show that the multi-leaf collimator produces clinically acceptable blocking for most field shapes and disease sites. The 80-20% penumbra was characterized for a wide range of shaped beams. For straight edges perpendicular to the leaf travel, the penumbra of measured dose distributions from the multi-leaf collimator is equal to conventional divergent blocking. When the multi-leaf collimator leaves approach a contour at an angle, the penumbra increases. At forty-five degrees, the maximum angle of approach, the penumbra is approximately 4 mm wider than that for divergent blocks. Three-dimensional treatment planning demonstrates that equivalent dose distributions can be obtained from the two field shaping systems. The multi-leaf collimator can be used effectively and efficiently to treat a variety of disease sites. Its optimal utility may be in treating complex fields--five or more shaped coplanar or non-coplanar beams. It is well suited for conformal therapy applications.

Neutron dosimetry intercomparison visits have been made by physicists from the M. D. Anderson Hospital-Texas A&M University Project to the Naval Research Laboratory, the University of Washington, and the MRC Cyclotron at Hammersmith Hospital. The Naval Research Laboratory and University of Washington physicists have made dosimetry intercomparisons at the Texas A&M Variable-Energy Cyclotron (TAMVEC). The parameters that are usually measured during these visits are tissue kerma in air, tissue dose at depth of dose maximum, relative central-axis depth dose, neutron/gamma ratios in air and in phantom, and photon calibrations of ionization chambers. In addition, beam profiles and dose buildup curves are sometimes measured. Other parameters that are compared are values of W, stopping power ratios, kerma corrections, and calculations that lead to the statement of tumor doses for patients. This paper presents some of the results of the intercomparisons and discusses the implications of the findings.

Forty-one patients with a total of 86 tumors were treated with negative pimesons (pions) at the Los Alamos Meson Physics Facility (LAMPF) through December 31, 1977. An additional 30 tumors in the total patient population were treated with 100 kVp x-rays to assess comparative effects on skin nodules and 8 patients received additive photon or electron radiation to pion-treated portals. Of 52 evaluable tumors in 20 patients treated with pions only and followed for 3 to 22 months, 81% (42 tumors) completely regressed; 6% (3 tumors) partially regressed; and 13% (7 tumors) did not respond, although 5 of the 7 have shown no growth for 10 months. Of eight tumors in seven patients treated with a combination of pions and conventional radiation, three tumors showed complete response and five tumors showed partial response, though the resected specimens in two (one with complete and one with partial response) revealed no tumor microscopically. Reactions in normal tissues have been mild, with some patients exhibiting no normal tissue reaction, as compared with relatively marked tumor response.

Procedures and techniques developed for the negative pi-meson (pion) radiotherapy program at the Los Alamos Meson Physics Facility, Los Alamos, NM, are reviewed and described. A particular pion patient is followed through the entire planning and treatment sequence to describe CT scanning procedures, bolus and collimator and treatment techniques developed to minimize positioning errors (less than 5 mm). Comparison of 2-D and 3-D isodose calculations developed at Los Alamos showed differences of less than 10% attributable to multiple scattering effects and the computational models used. Treatment verification methods using in vivo ion chamber dosimetry generally confirmed the prescribed dose delivery within 10% and using TLD within 18%.

Measurement of the effects of Telfon and air inhomogeneities on the ionization distributions of clinical negative-pion beams have been made at the Los Alamos Meson Physics Facility. Inhomogeneity location and pion-beam energy vary the effect of multiple coulomb scattering on the dose distribution lying in the penumbra of the inhomogeneity. CH2 bolus adequately corrects for the effects of these inhomogeneities. Bolus misalignment less than 0.5 cm does not seem critical because of large multiple coulomb scattering of the pion beam. However, this and secondary particles emitted from pion stars prevent the pion beam from being precisely shaped with sharp edges, as demonstrated by measurements under a patient bolus.

Cellular, animal, and human radiobiology studies are in progress at the Los Alamos Meson Physics Facility as part of a joint University of New Mexico and Los Alamos Scientific Laboratory pion therapy project. To support these activities, dosimetry has been performed on many different pion beam configurations. The effect of both static and dynamic momentum spreaders and of collimators on beam profiles, depth-dose distributions, and peak-to-plateau ratios have been studied. The absorbed dose is obtained by the application of Bragg-Gray cavity theory to ionization chamber measurements. Calculations have been made for the effective W values and average mass-stopping-power ratios needed for the Bragg-Gray equation. Kerma corrections are applied to transform the dose from the chamber wall to dose in muscle.

Two hundred twenty-eight patients were treated at the Los Alamos Meson Physics Facility (LAMPF) with negative pi-mesons (pions) between 1974 and 1981. Of these, 19 patients with metastatic disease were treated in pilot studies. Following the clinical determination of relative biological effectiveness (RBE) of pions, 209 patients were treated in site and dose searching studies beginning in 1977. Advanced but regionally localized cancers that were considered poorly responsive to conventional therapy were selected for treatment. A wide range of treatment fractions (22 to 45) and of total dose (1800 to 4200 cGy at the 80% isodose level) to the prescribed target volumes was explored. A follow-up observation period of between 4.5 and 9 years has been completed. The analysis focuses on 129 patients receiving pion therapy alone. Thirty-six (28%) had persisting local tumor control of which 12 (9%) suffered complications of treatment. The results varied among treatment sites, for example: prostate cancer, 18/21 (86%) locally controlled, 6/21 (29%) complications; head and neck, 8/31 (26%) locally controlled, 1/31 (3%) complications; and pancreas, none controlled and no complications. Analysis of dose-fraction response suggests a steep rising curve of complications beyond the dose level of 3750 cGy minimum, 4700 cGy maximum, in 38 fractions. The tumor control response has a broader and ill-defined curve possibly due to the heterogeneity of tumor types. The RBE for late effects in normal tissues appeared to be higher than that for acute effects although the mixture of tumor types, sites, dose, and fractionation made this estimate highly uncertain. No late secondary neoplastic changes in pion irradiated tissues were seen. It is concluded that pions can locally ablate some advanced cancers, often without significant sequelae, but that the optimum therapeutic range is critical. The Los Alamos data may be of use to ongoing pion studies in Canada and Switzerland.

Clinical investigations of pi meson radiotherapy were conducted by the Cancer Research and Treatment Center of the University of New Mexico and the Los Alamos National Laboratory from 1974 until 1982. Two hundred and thirty patients have been treated for a variety of locally advanced primary and metastatic neoplasms. One hundred and ninety-six patients have been followed for a minimum of 18 months. Crude survival data range from 11% for unresectable pancreatic carcinoma to 82% for Stages C and D1 adenocarcinoma of the prostate. Acute tolerance of normal tissues is approximately 4500 pion rad in 36 fractions over 7 weeks. Severe chronic reactions have appeared with increasing frequency after doses in excess of 4000 pion rad.

As a prelude to a randomized trial of negative pi meson (pion) radiotherapy, as compared to conventional radiation treatment, tolerance of several normal tissues was investigated. Fifty-three of 108 patients received at least 2700 peak pion rads at a usual dose rate between 100 and 125 rads daily. The major sites treated were head and neck, pancreas, prostate, rectum and brain. Acute normal tissue reactions, late effects, and tumor response are correlated with the two dose levels. Pancreatic tumors have not fared well. At this point, tumors that can be observed disappear more rapidly, and, for tumors that cannot be observed, symptoms disappear more rapidly and normal tissues exhibit less reaction than with conventional radiotherapy. It is believed that the dose level can be raised an additional 7 percent above the current 4100 rads, measured at the maximum within the treatment volume.