bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy
Authors: Mato Anthony R. , Roeker Lindsey E. , Jacobs Ryan , Hill Brian T. , Lamanna Nicole , Brander Danielle , Shadman Mazyar , Ujjani Chaitra S. , Yazdy Maryam Sarraf , Perini Guilherme Fleury , Pinilla-Ibarz Javier A. , Barrientos Jacqueline , Skarbnik Alan P. , Torka Pallawi , Pu Jeffrey J. , Pagel John M. , Gohil Satyen , Fakhri Bita , Choi Michael , Coombs Catherine C. , Rhodes Joanna , Barr Paul M. , Portell Craig A. , Parry Helen , Garcia Christine A. , Whitaker Kate J. , Winter Allison M. , Sitlinger Andrea , Khajavian Sirin , Grajales-Cruz Ariel F. , Isaac Krista M. , Shah Pratik , Akhtar Othman S. , Pocock Rachael , Lam Kentson , Voorhees Timothy J. , Schuster Stephen J. , Rodgers Thomas D. , Fox Christopher P. , Martinez-Calle Nicolas , Munir Talha , Bhavsar Erica B. , Bailey Neil , Lee Jason C. , Weissbrot Hanna B. , Nabhan Chadi , Goodfriend Julie M. , King Amber C. , Zelenetz Andrew D. , Dorsey Colleen , Bigelow Kayla , Cheson Bruce D. , Allan John N. , Eyre Toby A.
Published: April 2023

AbstractPurpose:
Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood.
Experimental Design:
To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies].
Results:
We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons.
Conclusions:
For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.

See related commentary by Rogers, p. 3501
Data from Patritumab with Cetuximab plus Platinum-Containing Therapy in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: An Open-Label, Phase Ib Study
Authors: Dillon Magnus T. , Grove Lorna , Newbold Kate L. , Shaw Heather , Brown Nicholas F. , Mendell Jeanne , Chen Shuquan , Beckman Robert A. , Jennings Anne , Ricamara Marivic , Greenberg Jonathan , Forster Martin , Harrington Kevin J.
Published: April 2023

AbstractPurpose:
Patritumab plus cetuximab with platinum as first-line therapy for patients with recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) was evaluated for safety and to determine the recommended phase II combination dose.
Patients and Methods:
Patients aged ≥18 years with confirmed R/M SCCHN received intravenous patritumab (18 mg/kg loading dose; 9 mg/kg maintenance dose every 3 weeks) + cetuximab (400 mg/m2 loading dose; 250 mg/m2 maintenance dose weekly) + cisplatin (100 mg/m2 every 3 weeks) or carboplatin (AUC of 5) for six cycles or until toxicity, disease progression, or withdrawal. Primary endpoints were dose-limiting toxicities [DLT; grade ≥3 (21-day observation period)] and treatment-emergent adverse events (TEAE). Pharmacokinetics, human antihuman antibodies (HAHA), tumor response, progression-free survival (PFS), and overall survival (OS) were assessed.
Results:
Fifteen patients completed a median (range) of 8.7 (2.0–20.7) patritumab cycles. No DLTs were reported. Serious adverse events were reported in 9 patients (patritumab-related n = 4). TEAEs (N = 15 patients) led to patritumab interruption in 7 patients. Patritumab-related dose reductions were reported in 1 patient. Patritumab (18 mg/kg) pharmacokinetics (N = 15) showed mean (SD) AUC0–21d of 2,619 (560) μg/day/mL and maximum concentration of 499.9 (90.4) μg/mL. All patients were HAHA-negative at study end (single, transient low titer in 1 patient). Tumor response rate (complete plus partial response; N = 15) was 47%. Median (95% confidence interval) PFS and OS (N = 15) were 7.9 (3.7–9.7) and 13.5 (6.6–17.5) months, respectively.
Conclusions:
Patritumab (18 mg/kg loading dose, 9 mg/kg maintenance dose) plus cetuximab/platinum was tolerable, active in SCCHN, and selected as the phase II dose regimen.
Data from Arming an Oncolytic Herpes Simplex Virus Type 1 with a Single-chain Fragment Variable Antibody against PD-1 for Experimental Glioblastoma Therapy
Authors: Passaro Carmela , Alayo Quazim , DeLaura Isabel , McNulty John , Grauwet Korneel , Ito Hirotaka , Bhaskaran Vivek , Mineo Marco , Lawler Sean E. , Shah Khalid , Speranza Maria C. , Goins William , McLaughlin Eric , Fernandez Soledad , Reardon David A. , Freeman Gordon J. , Chiocca E. Antonio , Nakashima Hiroshi
Published: April 2023

AbstractPurpose:
Glioblastoma (GBM) is resistant to standard of care. Immune checkpoints inhibitors (such as anti-PD-1 mAbs) efficiently restore antitumor T-cell activity. We engineered a new oncolytic herpes simplex virus (oHSV) expressing a single-chain antibody against PD-1 (scFvPD-1) to evaluate its efficacy in mouse models of GBM.
Experimental Design:
NG34scFvPD-1 expresses the human GADD34 gene transcriptionally controlled by the Nestin promoter to allow replication in GBM cells and a scFvPD-1 cDNA transcriptionally controlled by the CMV promoter. ELISA assays were performed to detect binding of scFvPD-1 to mouse and human PD-1. In vitro cytotoxicity and replication assays were performed to measure NG34scFvPD-1 oncolysis, and scFvPD-1 expression and secretion were determined. In vivo survival studies using orthotopic mouse GBM models were performed to evaluate the therapeutic potency of NG34scFvPD-1.
Results:
NG34scFvPD-1–infected GBM cells express and secrete scFvPD-1 that binds mouse PD-1. The introduction of the scFvPD-1 sequence in the viral backbone does not alter the oncolytic properties of NG34scFvPD-1. In situ NG34scFvPD-1 treatment improved the survival with a tail of durable survivorship in 2 syngeneic immunocompetent mouse models of GBM. Mice that survived the first GBM challenge rejected the second challenge of GBM when implanted in the contralateral hemisphere. However, this was not true when athymic mice were employed as the recipients of the second challenge, consistent with the need for an intact immune system to obtain a memory response.
Conclusions:
NG34scFvPD-1 treatment induces a durable antitumor response in 2 preclinical mouse models of GBM with evidence for antitumor memory.
Data from A Method to Summarize Toxicity in Cancer Randomized Clinical Trials
Authors: Carbini Mariana , Suárez-Fariñas Mayte , Maki Robert G.
Published: April 2023

Abstract
Purpose: Despite development of clinical “value frameworks” by national and international groups, there remains no generally accepted method to summarize toxicity in cancer clinical trials. We explored ways to simplify toxicity data of an arm of a cancer clinical trial to a single value, termed a “weighted toxicity score” (WTS).

Experimental Design: We compiled 58 randomized clinical trials of FDA-approved kinase-directed inhibitors. We generated 5 models, each of which assigned different weights for each observed grade 1 to 4 toxicities. For each model, we calculated WTS values as different weighted averages of the sum of the toxicities. We correlated each WTS with the dose reduction rate in each trial, using the dose reduction rate as a clinically relevant surrogate of treatment that is too toxic. The WTS method yielding the strongest correlation with frequency of dose reduction was declared the best model.

Results: Nineteen of 58 trials were placebo controlled and had complete data. Of the 5 models examined, differences in dose reduction rates correlated best with differences in WTS using a model with a clinician-weighted scale for toxicities (model M5). The WTS difference thus serves as a surrogate for a desired dose reduction rate difference and could be used to adjust dose/schedule as patients are accrued to a clinical trial.

Conclusions: The WTS distills a tabular listing of toxicities of a treatment into a single value, and provides a simple method that can be incorporated into value frameworks, or used to guide discussion of the risks and benefits of systemic therapy. Clin Cancer Res; 24(20); 4968–75. ©2018 AACR.

See related commentary by Vaishampayan, p. 4918
Data from Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers
Authors: Pozdeyev Nikita , Gay Laurie M. , Sokol Ethan S. , Hartmaier Ryan , Deaver Kelsi E. , Davis Stephanie , French Jena D. , Borre Pierre Vanden , LaBarbera Daniel V. , Tan Aik-Choon , Schweppe Rebecca E. , Fishbein Lauren , Ross Jeffrey S. , Haugen Bryan R. , Bowles Daniel W.
Published: April 2023

Abstract
Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer (ATC) and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.

Experimental Design: The genetic profiles of 583 advanced differentiated and 196 ATCs generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed.

Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared with other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated thyroid cancers and ATCs. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT, and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2, and JAK2, and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT, and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro. Three genetically distinct types of ATCs are proposed.

Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed. Clin Cancer Res; 24(13); 3059–68. ©2018 AACR.
Data from CDKN1B Deletions are Associated with Metastasis in African American Men with Clinically Localized, Surgically Treated Prostate Cancer
Authors: Faisal Farzana A. , Murali Sanjana , Kaur Harsimar , Vidotto Thiago , Guedes Liana B. , Salles Daniela Correia , Kothari Vishal , Tosoian Jeffrey J. , Han Sumin , Hovelson Daniel H. , Hu Kevin , Spratt Daniel E. , Baras Alexander S. , Tomlins Scott A. , Schaeffer Edward M. , Lotan Tamara L.
Published: April 2023

AbstractPurpose:
The potential biological determinants of aggressive prostate cancer in African American (AA) men are unknown. Here we characterize prostate cancer genomic alterations in the largest cohort to date of AA men with clinical follow-up for metastasis, with the aim to elucidate the key molecular drivers associated with poor prognosis in this population.
Experimental Design:
Targeted sequencing was retrospectively performed on 205 prostate tumors from AA men treated with radical prostatectomy (RP) to examine somatic genomic alterations and percent of the genome with copy-number alterations (PGA). Cox proportional hazards analyses assessed the association of genomic alterations with risk of metastasis.
Results:
At RP, 71% (145/205) of patients had grade group ≥3 disease, and 49% (99/202) were non–organ confined. The median PGA was 3.7% (IQR = 0.9%–9.4%) and differed by pathologic grade (P < 0.001) and stage (P = 0.02). Median follow-up was 5 years. AA men with the highest quartile of PGA had increased risks of metastasis (multivariable: HR = 13.45; 95% CI, 2.55–70.86; P = 0.002). The most common somatic mutations were SPOP (11.2%), FOXA1 (8.3%), and TP53 (3.9%). The most common loci altered at the copy number level were CDKN1B (6.3%), CHD1 (4.4%), and PTEN (3.4%). TP53 mutations and deep deletions in CDKN1B were associated with increased risks of metastasis on multivariable analyses (TP53: HR = 9.5; 95% CI, 2.2–40.6; P = 0.002; CDKN1B: HR = 6.7; 95% CI, 1.3–35.2; P = 0.026).
Conclusions:
Overall, PGA, somatic TP53 mutations, and a novel finding of deep deletions in CDKN1B were associated with poor prognosis in AA men. These findings require confirmation in additional AA cohorts.
Data from Telomerase Reverse Transcriptase Promoter Mutations Identify a Genomically Defined and Highly Aggressive Human Pleural Mesothelioma Subgroup
Authors: Pirker Christine , Bilecz Agnes , Grusch Michael , Mohr Thomas , Heidenreich Barbara , Laszlo Viktoria , Stockhammer Paul , Lötsch-Gojo Daniela , Gojo Johannes , Gabler Lisa , Spiegl-Kreinecker Sabine , Dome Balazs , Steindl Ariane , Klikovits Thomas , Hoda Mir Alireza , Jakopovic Marko , Samarzija Miroslav , Mohorcic Katja , Kern Izidor , Kiesel Barbara , Brcic Luka , Oberndorfer Felicitas , Müllauer Leonhard , Klepetko Walter , Schmidt Wolfgang M. , Kumar Rajiv , Hegedus Balazs , Berger Walter
Published: April 2023

AbstractPurpose:
Human malignant pleural mesothelioma (MPM) is characterized by dismal prognosis. Consequently, dissection of molecular mechanisms driving malignancy is of key importance. Here we investigate whether activating mutations in the telomerase reverse transcriptase (TERT) gene promoter are present in MPM and associated with disease progression, cell immortalization, and genomic alteration patterns.
Experimental Design:
TERT promoters were sequenced in 182 MPM samples and compared with clinicopathologic characteristics. Surgical specimens from 45 patients with MPM were tested for in vitro immortalization. The respective MPM cell models (N = 22) were analyzed by array comparative genomic hybridization, gene expression profiling, exome sequencing as well as TRAP, telomere length, and luciferase promoter assays.
Results:
TERT promoter mutations were detected in 19 of 182 (10.4%) MPM cases and significantly associated with advanced disease and nonepithelioid histology. Mutations independently predicted shorter overall survival in both histologic MPM subtypes. Moreover, 9 of 9 (100%) mutated but only 13 of 36 (36.1%) wild-type samples formed immortalized cell lines. TERT promoter mutations were associated with enforced promoter activity and TERT mRNA expression, while neither telomerase activity nor telomere lengths were significantly altered. TERT promoter–mutated MPM cases exhibited distinctly reduced chromosomal alterations and specific mutation patterns. While BAP1 mutations/deletions were exclusive with TERT promoter mutations, homozygous deletions at the RBFOX1 and the GSTT1 loci were clearly enriched in mutated cases.
Conclusions:
TERT promoter mutations independently predict a dismal course of disease in human MPM. The altered genomic aberration pattern indicates that TERT promoter mutations identify a novel, highly aggressive MPM subtype presumably based on a specific malignant transformation process.
Data from Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma
Authors: Ishida Chiaki T. , Zhang Yiru , Bianchetti Elena , Shu Chang , Nguyen Trang T.T. , Kleiner Giulio , Sanchez-Quintero Maria J. , Quinzii Catarina M. , Westhoff Mike-Andrew , Karpel-Massler Georg , Prabhu Varun V. , Allen Joshua E. , Siegelin Markus D.
Published: April 2023

Abstract
Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM).

Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency.

Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo. ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells in vitro and in vivo. Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo.

Conclusions: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies. Clin Cancer Res; 24(21); 5392–406. ©2018 AACR.
Data from Induced Tumor Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations
Authors: Aguilera Todd A. , Elghonaimy Eslam A. , Shehade Hussein , Rafat Marjan , Castellini Laura , Jiang Dadi , Kariolis Mihalis , Koong Albert C. , Le Quynh-Thu , Ellies Lesley G. , Rankin Erinn B. , Graves Edward E. , Giaccia Amato J.
Published: April 2023

AbstractPurpose:
To investigate how induced tumor heterogeneity influences immune responses to radiotherapy with different proportions of mixed immune-responsive and unresponsive tumor cells in a triple-negative breast cancer model. It is hypothesized that studying the immune environment of mixed tumors and responses to radiotherapy could nominate immune active therapies to enhance immune responses after radiotherapy.
Experimental Design:
Evaluate efficacy and immune responses generated by radiotherapy in tumors with different proportions of immunologically responsive and unresponsive tumor cells. Then study the cellular responses and transcriptomic differences between the tumors to nominate immunotherapy combinations with radiotherapy and evaluate the combination.
Results:
The addition of the responsive cells to unresponsive tumors led to a greater than expected therapeutic response to radiotherapy with both innate and adaptive immune components. There was a distinct change in myeloid cells, greater inflammatory macrophage activity, and enhanced antigen presentation with responsive cells after radiotherapy. Because differences in matrix components, cell adhesion biology, and innate immune signaling correlated with myeloid cell response and phenotype, we hypothesized that radiotherapy combined with CD40 agonist antibody would sensitize unresponsive tumors. The combination therapy resulted in improved innate and adaptive immune response. Importantly, CD40 treatment increased tumor response to radiotherapy and protected against metastatic spread in a metastatic model.
Conclusions:
These data combined with transcriptomics from human patients support radiotherapy and myeloid cell targeting for immunologically cold tumors. The established study model presents opportunities to investigate the complex overlapping biologic mechanisms that limit immunotherapy and to implement radiotherapy with different immunotherapy combinations.
Data from Concurrent Definitive Immunoradiotherapy for Patients with Stage III–IV Head and Neck Cancer and Cisplatin Contraindication
Authors: Weiss Jared , Sheth Siddharth , Deal Allision M. , Grilley Olson Juneko E. , Patel Samip , Hackman Trevor G. , Blumberg Jeffrey M. , Galloway Thomas J. , Patel Shetal , Zanation Adam M. , Shen Colette J. , Hayes D. Neil , Hilliard Christopher , Mehra Ranee , McKinnon Karen P. , Wang Hsing-Hui , Weissler Mark Christian , Bauman Jessica R. , Chera Bhishamjit S. , Vincent Benjamin G.
Published: April 2023

AbstractPurpose:
Although cisplatin plus radiotherapy is a standard treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC), cisplatin contraindication is common. Radiation elicits and promotes tumor-directed immune stimulation, which may potentiate anti–PD-1 therapy. We provide the first efficacy report of combined pembrolizumab and definitive radiotherapy in LA-HNSCC.
Patients and Methods:
This single-arm, multi-institution, phase II study (NCT02609503) enrolled 29 cisplatin-ineligible patients. Patients received radiotherapy concurrently with three cycles of pembrolizumab 200 mg every 3 weeks followed by three adjuvant cycles. The primary endpoint was a progression-free survival (PFS) of ≥16 months. Correlative studies included peripheral blood flow cytometry and Luminex cytokine profiling.
Results:
Reasons for cisplatin ineligibility included otopathy (69.0%), nephropathy (20.7%), and neuropathy (6.9%). With median follow-up of 21 months, estimated 24-month PFS and overall survival rates were 71% (95% confidence interval, 49%–84%) and 75% (51%–88%). The primary PFS endpoint has exceeded the hypothesis and its median has not been reached. Toxicities were typical of radiotherapy; however, high rates of grade 3/4 lymphopenia (58.6%) were observed. Flow cytometry revealed a relative decline in CD4 T cells and B cells, but not CD8 T cells. Upon treatment, frequencies of transitional B cells and tissue-like memory B cells increased, while resting memory B cells decreased. Patients with progression had greater percentages of baseline naïve B cells and fewer marginal zone B cells.
Conclusions:
Pembrolizumab and radiotherapy is efficacious in LA-HNSCC and should be evaluated in a randomized trial. The observed changes in B-cell markers deserve further study both as potential biomarkers and as therapeutic targets.
Data from Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer
Authors: Wu Christina , Williams Terence M. , Robb Ryan , Webb Amy , Wei Lai , Chen Wei , Mikhail Sameh , Ciombor Kristen K. , Cardin Dana B. , Timmers Cynthia , Krishna Somashekar G. , Arnold Mark , Harzman Alan , Abdel-Misih Sherif , Roychowdhury Sameek , Bekaii-Saab Tanios , Wuthrick Evan
Published: April 2023

AbstractPurpose:
The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).
Patients and Methods:
Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.
Results:
Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.
Conclusions:
The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.
Data from Targeted Natural Killer Cell–Based Adoptive Immunotherapy for the Treatment of Patients with NSCLC after Radiochemotherapy: A Randomized Phase II Clinical Trial
Authors: Multhoff Gabriele , Seier Sophie , Stangl Stefan , Sievert Wolfgang , Shevtsov Maxim , Werner Caroline , Pockley A. Graham , Blankenstein Christiane , Hildebrandt Martin , Offner Robert , Ahrens Norbert , Kokowski Konrad , Hautmann Matthias , Rödel Claus , Fietkau Rainer , Lubgan Dorota , Huber Rudolf , Hautmann Hubert , Duell Thomas , Molls Michael , Specht Hanno , Haller Bernhard , Devecka Michal , Sauter Andreas , Combs Stephanie E.
Published: April 2023

AbstractPurpose:
Non–small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. A membrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo–activated NK cells in patients with NSCLC after radiochemotherapy (RCT).
Patients and Methods:
Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60–70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses.
Results:
The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%–90%] for the INT arm and 33% (95% CI, 5%–68%) for the CTRL arm (P = 0.36, 1-sided log-rank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood.
Conclusions:
Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.
Data from Effect of Germline Mutations in Homologous Recombination Repair Genes on Overall Survival of Patients with Pancreatic Adenocarcinoma
Authors: Yadav Siddhartha , Kasi Pashtoon M. , Bamlet William R. , Ho Thanh P. , Polley Eric C. , Hu Chunling , Hart Steven N. , Rabe Kari G. , Boddicker Nicholas J. , Gnanaolivu Rohan D. , Lee Kun Y. , Lindstrom Tricia H. , Petersen Gloria M. , Couch Fergus J. , McWilliams Robert R.
Published: April 2023

AbstractPurpose:
To compare the clinical characteristics and overall survival (OS) of germline mutation carriers in homologous recombination repair (HRR) genes and noncarriers with pancreatic ductal adenocarcinoma (PDAC).
Experimental Design:
Germline DNA from 3,078 patients with PDAC enrolled in a prospective registry at Mayo Clinic between 2000 and 2017 was analyzed for mutations in 37 cancer predisposition genes. Characteristics and OS of patients with mutations in eight genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, PALB2, RAD51C, and RAD51D) involved in HRR were compared with patients testing negative for mutations in all 37 genes.
Results:
The 175 HRR mutation carriers and 2,730 noncarriers in the study had a median duration of follow-up of 9.9 years. HRR mutation carriers were younger (median age at diagnosis: 63 vs. 66 years, P < 0.001) and more likely to have metastatic disease at diagnosis (46% vs. 36%, P = 0.004). In a multivariable model adjusting for sex, age at diagnosis, and tumor staging, patients with germline HRR mutations had a significantly longer OS compared with noncarriers [HR, 0.83; 95% confidence interval (CI), 0.70–0.97; P = 0.02]. Further gene-level analysis demonstrated that germline ATM mutation carriers had longer OS compared with patients without germline mutations in any of the 37 genes (HR, 0.72; 95% CI, 0.55–0.94; P = 0.01).
Conclusions:
This study demonstrates that germline mutation carrier status in PDAC is associated with longer OS compared with noncarriers. Further research into tumor biology and response to platinum-based chemotherapy in germline mutation carriers with PDAC are needed to better understand the association with longer OS.
Data from Outcome-Related Signatures Identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated after Starting Hu14.18-IL2
Authors: Yang Richard K. , Kuznetsov Igor B. , Ranheim Erik A. , Wei Jun S. , Sindiri Sivasish , Gryder Berkley E. , Gangalapudi Vineela , Song Young K. , Patel Viharkumar , Hank Jacquelyn A. , Zuleger Cindy , Erbe Amy K. , Morris Zachary S. , Quale Renae , Kim KyungMann , Albertini Mark R. , Khan Javed , Sondel Paul M.
Published: April 2023

AbstractPurpose:
We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in patients with melanoma at high risk for recurrence.
Experimental Design:
Patients were randomly assigned to receive the first of three monthly courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known diseases. Tumors were evaluated by histology and whole transcriptome sequencing.
Results:
Tumor-infiltrating lymphocyte (TIL) levels directly associated with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature, which associated with RFS and OS, particularly in Group A tumors. In Group A tumors, there were decreased cell-cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth–associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors.
Conclusions:
We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNA-sequencing analyses detected shortly after initiation of hu14.18-IL2 therapy, are associated with long-term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy.
Data from Ibrutinib Treatment for First-Line and Relapsed/Refractory Chronic Lymphocytic Leukemia: Final Analysis of the Pivotal Phase Ib/II PCYC-1102 Study
Authors: Byrd John C. , Furman Richard R. , Coutre Steven E. , Flinn Ian W. , Burger Jan A. , Blum Kristie , Sharman Jeff P. , Wierda William , Zhao Weiqiang , Heerema Nyla A. , Luan Ying , Liu Emily A. , Dean James P. , O'Brien Susan
Published: April 2023

AbstractPurpose:
The safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date.
Patients and Methods:
Phase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL.
Results:
Overall response rate was 89%, with similar rates in first-line (87%; complete response, 35%) and relapsed/refractory settings (89%; 10%). Estimated 7-year progression-free survival (PFS) rates were 83% in first-line and 34% in relapsed/refractory settings. Forty-one patients had CLL progression (n = 11 with Richter's transformation). Median PFS was not reached with first-line ibrutinib. In relapsed/refractory CLL/SLL, median PFS was 52 months overall, 26 months in patients with chromosome 17p deletion, 51 months with 11q deletion, not reached with trisomy 12 or 13q deletion, and 88 months in patients without these cytogenetic abnormalities. Estimated 7-year overall survival rates were 84% in first-line and 55% in relapsed/refractory settings. Grade ≥3 adverse events (AE) in >15% of patients were hypertension (28%), pneumonia (24%), and neutropenia (18%). These grade ≥3 AEs generally declined over time, except hypertension. AEs leading to discontinuation in ≥2 patients were observed only in the relapsed/refractory setting (sepsis, diarrhea, subdural hematoma, and Richter's transformation).
Conclusions:
With up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.
Data from Phase I Trial of Debio 1143, an Antagonist of Inhibitor of Apoptosis Proteins, Combined with Cisplatin Chemoradiotherapy in Patients with Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Authors: Le Tourneau Christophe , Tao Yungan , Gomez-Roca Carlos , Cristina Valerie , Borcoman Edith , Deutsch Eric , Bahleda Rastislav , Calugaru Valentin , Modesto Anouchka , Rouits Elisabeth , Gollmer Kathrin , Vuagniaux Gregoire , Crompton Philippa , Zanna Claudio , Szyldergemajn Sergio , Delord Jean-Pierre , Bourhis Jean
Published: April 2023

AbstractPurpose:
Debio 1143 is an oral antagonist of inhibitor of apoptosis proteins, which enhances tumor response with concomitant chemoradiotherapy. Addition of Debio 1143 to cisplatin-based chemoradiotherapy in locally advanced squamous cell carcinomas of the head and neck (LA-SCCHN) was evaluated in a phase I/II study to determine the MTD and recommended phase II dose (RP2D). Here, phase I results are reported.
Patients and Methods:
Treatment-naïve patients with LA-SCCHN (stages III/IVA/IVB) received Debio 1143 (100, 200, 300 mg/day), for 14 days every 3 weeks, with cisplatin (100 mg/m², every 3 weeks), for three cycles, and concomitant conventional fractionation radiotherapy (70 Gy/7 weeks). Dose-limiting toxicity (DLT) was evaluated over 9 weeks using continual reassessment.
Results:
Fourteen patients were treated/evaluable for DLT. Median age was 64.5 years, and all patients were current/former smokers. Primary tumors were hypopharynx, oropharynx (all human papillomavirus/p16 negative), larynx, and oral cavity. Two of six patients at 200 mg/day had DLT (grade 3 tubular necrosis, grade 3 aspartate aminotransferase/alanine aminotransferase increase, grade 4 febrile neutropenia, and grade 3 lipase increase), which was considered the MTD and RP2D. Common grade 3–4 adverse events were dysphagia (36%) and mucositis (29%). Laboratory abnormalities were frequent and generally mild, including anemia, white blood cell decrease, and increased creatinine. Addition of Debio 1143 did not compromise chemotherapy administration. Overall locoregional control rate at 18 months was 85%. Overall response rate was 85%, including 69% complete responses. Progression-free survival rate at 24 months was 74%.
Conclusions:
The RP2D of Debio 1143 is 200 mg/day for 14 days, every 3 weeks, when combined with concomitant high-dose cisplatin chemoradiotherapy in LA-SCCHN. Debio 1143 addition to chemoradiotherapy was safe and manageable. Preliminary efficacy is encouraging and supports further development.
Data from Mutation-derived Neoantigen-specific T-cell Responses in Multiple Myeloma
Authors: Perumal Deepak , Imai Naoko , Laganà Alessandro , Finnigan John , Melnekoff David , Leshchenko Violetta V. , Solovyov Alexander , Madduri Deepu , Chari Ajai , Cho Hearn Jay , Dudley Joel T. , Brody Joshua D. , Jagannath Sundar , Greenbaum Benjamin , Gnjatic Sacha , Bhardwaj Nina , Parekh Samir
Published: April 2023

AbstractPurpose:
Somatic mutations in cancer cells can give rise to novel protein sequences that can be presented by antigen-presenting cells as neoantigens to the host immune system. Tumor neoantigens represent excellent targets for immunotherapy, due to their specific expression in cancer tissue. Despite the widespread use of immunomodulatory drugs and immunotherapies that recharge T and NK cells, there has been no direct evidence that neoantigen-specific T-cell responses are elicited in multiple myeloma.
Experimental Design:
Using next-generation sequencing data we describe the landscape of neo-antigens in 184 patients with multiple myeloma and successfully validate neoantigen-specific T cells in patients with multiple myeloma and support the feasibility of neoantigen-based therapeutic vaccines for use in cancers with intermediate mutational loads such as multiple myeloma.
Results:
In this study, we demonstrate an increase in neoantigen load in relapsed patients with multiple myeloma as compared with newly diagnosed patients with multiple myeloma. Moreover, we identify shared neoantigens across multiple patients in three multiple myeloma oncogenic driver genes (KRAS, NRAS, and IRF4). Next, we validate neoantigen T-cell response and clonal expansion in correlation with clinical response in relapsed patients with multiple myeloma. This is the first study to experimentally validate the immunogenicity of predicted neoantigens from next-generation sequencing in relapsed patients with multiple myeloma.
Conclusions:
Our findings demonstrate that somatic mutations in multiple myeloma can be immunogenic and induce neoantigen-specific T-cell activation that is associated with antitumor activity in vitro and clinical response in vivo. Our results provide the foundation for using neoantigen targeting strategies such as peptide vaccines in future trials for patients with multiple myeloma.
Data from The Effects of a Remote-based Weight Loss Program on Adipocytokines, Metabolic Markers, and Telomere Length in Breast Cancer Survivors: the POWER-Remote Trial
Authors: Santa-Maria Cesar A. , Coughlin Janelle W. , Sharma Dipali , Armanios Mary , Blackford Amanda L. , Schreyer Colleen , Dalcin Arlene , Carpenter Ashley , Jerome Gerald J. , Armstrong Deborah K. , Chaudhry Madhu , Cohen Gary I. , Connolly Roisin M. , Fetting John , Miller Robert S. , Smith Karen L. , Snyder Claire , Wolfe Andrew , Wolff Antonio C. , Huang Chiung-Yu , Appel Lawrence J. , Stearns Vered
Published: April 2023

AbstractPurpose:
We initiated a clinical trial to determine the proportion of breast cancer survivors achieving ≥5% weight loss using a remotely delivered weight loss intervention (POWER-remote) or a self-directed approach, and to determine the effects of the intervention on biomarkers of cancer risk including metabolism, inflammation, and telomere length.
Experimental Design:
Women with stage 0–III breast cancer, who completed local therapy and chemotherapy, with a body mass index ≥25 kg/m2 were randomized to a 12-month intervention (POWER-remote) versus a self-directed approach. The primary objective was to determine the number of women who achieved at least 5% weight loss at 6 months. We assessed baseline and 6-month change in a panel of adipocytokines (adiponectin, leptin, resistin, HGF, NGF, PAI1, TNFα, MCP1, IL1β, IL6, and IL8), metabolic factors (insulin, glucose, lipids, hs-CRP), and telomere length in peripheral blood mononuclear cells.
Results:
From 2013 to 2015, 96 women were enrolled, and 87 were evaluable for the primary analysis; 45 to POWER-remote and 42 to self-directed. At 6 months, 51% of women randomized to POWER-remote lost ≥5% of their baseline body weight, compared with 12% in the self-directed arm [OR, 7.9; 95% confidence interval (CI), 2.6–23.9; P = 0.0003]; proportion were similar at 12 months (51% vs 17%, respectively, P = 0.003). Weight loss correlated with significant decreases in leptin, and favorable modulation of inflammatory cytokines and lipid profiles. There was no significant change in telomere length at 6 months.
Conclusions:
A remotely delivered weight loss intervention resulted in significant weight loss in breast cancer survivors, and favorable effects on several biomarkers.
Data from Immune Escape After Adoptive T-cell Therapy for Malignant Gliomas
Authors: Wildes Tyler J. , Dyson Kyle A. , Francis Connor , Wummer Brandon , Yang Changlin , Yegorov Oleg , Shin David , Grippin Adam , Dean Bayli DiVita , Abraham Rebecca , Pham Christina , Moore Ginger , Kuizon Carmelle , Mitchell Duane A. , Flores Catherine T.
Published: April 2023

AbstractPurpose:
Immunotherapy has been demonstrably effective against multiple cancers, yet tumor escape is common. It remains unclear how brain tumors escape immunotherapy and how to overcome this immune escape.
Experimental Design:
We studied KR158B-luc glioma-bearing mice during treatment with adoptive cellular therapy (ACT) with polyclonal tumor-specific T cells. We tested the immunogenicity of primary and escaped tumors using T-cell restimulation assays. We used flow cytometry and RNA profiling of whole tumors to further define escape mechanisms. To treat immune-escaped tumors, we generated escape variant-specific T cells through the use of escape variant total tumor RNA and administered these cells as ACT. In addition, programmed cell death protein-1 (PD-1) checkpoint blockade was studied in combination with ACT.
Results:
Escape mechanisms included a shift in immunogenic tumor antigens, downregulation of MHC class I, and upregulation of checkpoint molecules. Polyclonal T cells specific for escape variants displayed greater recognition of escaped tumors than primary tumors. When administered as ACT, these T cells prolonged median survival of escape variant-bearing mice by 60%. The rational combination of ACT with PD-1 blockade prolonged median survival of escape variant glioma-bearing mice by 110% and was dependent upon natural killer cells and T cells.
Conclusions:
These findings suggest that the immune landscape of brain tumors are markedly different postimmunotherapy yet can still be targeted with immunotherapy.
Data from First-in-Human Assessment of cRGD-ZW800-1, a Zwitterionic, Integrin-Targeted, Near-Infrared Fluorescent Peptide in Colon Carcinoma
Authors: de Valk Kim S. , Deken Marion M. , Handgraaf Henricus J.M. , Bhairosingh Shadhvi S. , Bijlstra Okker D. , van Esdonk Michiel J. , Terwisscha van Scheltinga Anton G.T. , Valentijn A. Rob P.M. , March Taryn L. , Vuijk Jaap , Peeters Koen C.M.J. , Holman Fabian A. , Hilling Denise E. , Mieog J. Sven D. , Frangioni John V. , Burggraaf Jacobus , Vahrmeijer Alexander L.
Published: April 2023

AbstractPurpose:
Incomplete oncologic resections and damage to vital structures during colorectal cancer surgery increases morbidity and mortality. Moreover, neoadjuvant chemoradiotherapy has become the standard treatment modality for locally advanced rectal cancer, where subsequent downstaging can make identification of the primary tumor more challenging during surgery. Near-infrared (NIR) fluorescence imaging can aid surgeons by providing real-time visualization of tumors and vital structures during surgery.
Experimental Design:
We present the first-in-human clinical experience of a novel NIR fluorescent peptide, cRGD-ZW800-1, for the detection of colon cancer. cRGD-ZW800-1 was engineered to have an overall zwitterionic chemical structure and neutral charge to lower nonspecific uptake and thus background fluorescent signal. We performed a phase I study in 11 healthy volunteer as well as a phase II feasibility study in 12 patients undergoing an elective colon resection, assessing 0.005, 0.015, and 0.05 mg/kg cRGD-ZW800-1 for the intraoperative visualization of colon cancer.
Results:
cRGD-ZW800-1 appears safe, and exhibited rapid elimination into urine after a single low intravenous dose. Minimal invasive intraoperative visualization of colon cancer through full-thickness bowel wall was possible after an intravenous bolus injection of 0.05 mg/kg at least 2 hours prior to surgery. Longer intervals between injection and imaging improved the tumor-to-background ratio.
Conclusions:
cRGD-ZW800-1 enabled fluorescence imaging of colon cancer in both open and minimal invasive surgeries. Further development of cRGD-ZW800-1 for widespread use in cancer surgery may be warranted given the ubiquitous overexpression of various integrins on different types of tumors and their vasculature.
Data from X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis
Authors: Tricarico Rossella , Nicolas Emmanuelle , Hall Michael J. , Golemis Erica A.
Published: April 2023

Abstract
Biological sex profoundly conditions organismal development and physiology, imposing wide-ranging effects on cell signaling, metabolism, and immune response. These effects arise from sex-specified differences in hormonal exposure, and from intrinsic genetic and epigenetic differences associated with the presence of an XX versus XY chromosomal complement. In addition, biological sex is now recognized to be a determinant of the incidence, presentation, and therapeutic response of multiple forms of cancer, including cancers not specifically associated with male or female anatomy. Although multiple factors contribute to sex-based differences in cancer, a growing body of research emphasizes a role for differential activity of X- and Y-linked tumor-suppressor genes in males and females. Among these, the X-linked KDM6A/UTX and KDM5C/JARID1C/SMCX, and their Y-linked paralogs UTY/KDM6C and KDM5D/JARID1D/SMCY encode lysine demethylases. These epigenetic modulators profoundly influence gene expression, based on enzymatic activity in demethylating H3K27me3 and H3K4me3, and nonenzymatic scaffolding roles for large complexes that open and close chromatin for transcription. In a growing number of cases, mutations affecting these proteins have been recognized to strongly influence cancer risk, prognosis, and response to specific therapies. However, sex-specific patterns of mutation, expression, and activity of these genes, coupled with tissue-specific requirement for their function as tumor suppressors, together exemplify the complex relationship between sex and cancer vulnerabilities. In this review, we summarize and discuss the current state of the literature on the roles of these proteins in contributing to sex bias in cancer, and the status of clinical agents relevant to their function.