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1.
Mol Ther ; 32(9): 2979-2983, 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-38532629

RESUMEN

With expansion of chimeric antigen receptor (CAR) T cell therapy and broader utilization of anti-cytokine directed therapeutics for toxicity mitigation, the routine assessment of cytokines may enhance understanding of toxicity profiles, guide therapeutic interventions, and facilitate cross-trial comparisons. As specific cytokine elevations can correlate with and provide insights into CAR T cell toxicity, mitigation strategies, and response, we explored the reporting of cytokine detection methods and assessed for the correlation of cytokines to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) across clinical trials. In this analysis, we reviewed 21 clinical trials across 60 manuscripts that featured a US Food and Drug Administration-approved CAR T cell construct or one of its predecessors. We highlight substantial variability and limited reporting of cytokine measurement platforms and panels used across CAR T cell clinical trials. Specifically, across 60 publications, 28 (46.7%) did not report any cytokine data, representing 6 of 21 (28.6%) clinical trials. In the 15 trials reporting cytokine data, at least 4 different platforms were used. Furthermore, correlation of cytokines with ICANS, CRS, and CRS severity was limited. Considering the fundamental role of cytokines in CAR T cell toxicity, our manuscript supports the need to establish standardization of cytokine measurements as a key biomarker essential to improving outcomes of CAR T cell therapy.


Asunto(s)
Ensayos Clínicos como Asunto , Síndrome de Liberación de Citoquinas , Citocinas , Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Humanos , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Citocinas/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Síndrome de Liberación de Citoquinas/terapia , Síndrome de Liberación de Citoquinas/etiología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/terapia , Síndromes de Neurotoxicidad/diagnóstico , Receptores de Antígenos de Linfocitos T/metabolismo , Biomarcadores
2.
Curr Opin Hematol ; 29(4): 225-232, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35787551

RESUMEN

PURPOSE OF REVIEW: The purpose of this review is to summarize the status and utilization of chimeric antigen receptor T-cell (CAR-T) therapy based on the most recent clinical trials in patients with leukemia and lymphoma. Additionally, this review will highlight limitations in current strategies, discuss efforts in toxicity mitigation, and outline future directions for investigation. RECENT FINDINGS: CD19 targeted CAR-T-cell therapy (CD19-CAR) is highly effective in patients with relapsed/refractory (r/r) B-cell hematologic malignancies. However, multiple challenges have arisen, particularly life-threatening adverse events, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Despite these challenges, recent CD19-CAR trials, including two randomized studies, have demonstrated both impressive initial results along with durable responses. Combined with results emerging from 'real-world' experience, the efficacy of CAR-T-cells is high, propelling CAR-T-cells studies targeting alternate B-cell antigens [e.g. CD20, CD22 and CD269 (BCMA)] and other targets for hematologic malignancies, along with solid and CNS tumors. SUMMARY: Given the benefit for CD19-CAR, determining the appropriate place in utilization for both an individual patient's treatment course and more broadly in the generalized treatment paradigm is critically needed. We discuss the most recent trials exploring this topic and future directions in the field.


Asunto(s)
Neoplasias Hematológicas , Receptores Quiméricos de Antígenos , Antígenos CD19 , Tratamiento Basado en Trasplante de Células y Tejidos , Neoplasias Hematológicas/terapia , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Receptores Quiméricos de Antígenos/genética
3.
Curr Treat Options Oncol ; 23(12): 1861-1876, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36380108

RESUMEN

OPINION STATEMENT: While no PD-1 inhibitor has been FDA approved for use in sarcoma or proven efficacious in a randomized trial, the use of single agent PD-1 inhibitors is standard-of-care and recommended by the NCCN guidelines in certain specific subtypes and situations. Even while the role of immunotherapy is still being defined in sarcoma, there is rising interest in combinations of PD-1 inhibitors with standard-of-care treatments, especially chemotherapy. Recently, several early phase trials have suggested potential benefits for chemotherapy in combination with PD-1 inhibitors. Although some physicians are already combining PD-1 inhibitors and chemotherapy for sarcoma off-label in the community, we believe more data is necessary. We support further evaluation of these combinations in well-designed clinical trials.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Sarcoma , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Sarcoma/tratamiento farmacológico , Inmunoterapia , Antígeno B7-H1
4.
bioRxiv ; 2024 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-39416100

RESUMEN

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized well-annotated rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive transcriptomic and epigenomic analyses, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

5.
BMC Genomics ; 14: 818, 2013 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-24261984

RESUMEN

BACKGROUND: RNA-seq has spurred important gene fusion discoveries in a number of different cancers, including lung, prostate, breast, brain, thyroid and bladder carcinomas. Gene fusion discovery can potentially lead to the development of novel treatments that target the underlying genetic abnormalities. RESULTS: In this study, we provide comprehensive view of gene fusion landscape in 185 glioblastoma multiforme patients from two independent cohorts. Fusions occur in approximately 30-50% of GBM patient samples. In the Ivy Center cohort of 24 patients, 33% of samples harbored fusions that were validated by qPCR and Sanger sequencing. We were able to identify high-confidence gene fusions from RNA-seq data in 53% of the samples in a TCGA cohort of 161 patients. We identified 13 cases (8%) with fusions retaining a tyrosine kinase domain in the TCGA cohort and one case in the Ivy Center cohort. Ours is the first study to describe recurrent fusions involving non-coding genes. Genomic locations 7p11 and 12q14-15 harbor majority of the fusions. Fusions on 7p11 are formed in focally amplified EGFR locus whereas 12q14-15 fusions are formed by complex genomic rearrangements. All the fusions detected in this study can be further visualized and analyzed using our website: http://ivygap.swedish.org/fusions. CONCLUSIONS: Our study highlights the prevalence of gene fusions as one of the major genomic abnormalities in GBM. The majority of the fusions are private fusions, and a minority of these recur with low frequency. A small subset of patients with fusions of receptor tyrosine kinases can benefit from existing FDA approved drugs and drugs available in various clinical trials. Due to the low frequency and rarity of clinically relevant fusions, RNA-seq of GBM patient samples will be a vital tool for the identification of patient-specific fusions that can drive personalized therapy.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Glioblastoma/genética , Proteínas de Fusión Oncogénica/genética , Transcriptoma/genética , Perfilación de la Expresión Génica , Glioblastoma/patología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recurrencia Local de Neoplasia/genética , Proteínas de Fusión Oncogénica/clasificación , Proteínas de Fusión Oncogénica/aislamiento & purificación
6.
Cancers (Basel) ; 15(23)2023 Nov 26.
Artículo en Inglés | MEDLINE | ID: mdl-38067292

RESUMEN

BACKGROUND: Both gemcitabine- and 5-fluorouracil (5-FU)-based chemotherapy regimens have demonstrated efficacy in metastatic pancreatic cancer (MPC). Alternating these regimens may reduce toxicity, slow resistant cancer biology emergence, and provide a platform for the addition of other therapeutic agents. Alternating gemcitabine/nab-paclitaxel (GA) and 5-FU/leucovorin/irinotecan (FOLFIRI) in MPC has previously been reported at our own institution and elsewhere. An extension of our institutional observations is reported here. METHODS: Patient eligibility required the following: biopsy-proven de novo MPC, no prior evidence of disease on CT, ECOG performance status (PS) ≤ 2, and bi-dimensionally measurable disease. Treatment (Tx) entailed gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2 1, (8), 15 alternating every 8 weeks (2 cycles) with FOLFIRI using standard dosing. Patients were radiographically re-staged every 8 weeks. Tx spanned up to 12 cycles. Tx thereafter was decided following patient/physician discussion. RESULTS: Median overall survival (mOS) was 13.2 months (95% CI 10.9-16.5 months). Median progression-free survival (mPFS) was 8.5 months (95% CI, 7.1-9.9). The 6-, 12-, 18-, and 24-month OS rates were 88%, 54%, 36%, and 20%, respectively. The disease control rate at 16 weeks was 83% (37% PR, 46% SD). Hematologic toxicity grade ≥ 3 included 9.3% anemia, 10.2% neutropenia, and 4.6% thrombocytopenia. Neutrophil growth factors were not used in this cohort. Non-hematologic toxicities grade ≥ 3 included neuropathy 0.9%, nausea/vomiting 0.9%, and diarrhea 0.9%. No patients experienced mucositis on this regimen. CONCLUSIONS: Alternating GA/FOLFIRI in MPC has a favorable toxicity profile in comparison to current standard regimens. Median OS was at least competitive with standard regimens, and longer-term (18 and 24 months) OS seemed particularly encouraging. Treatment for ≥48 weeks and ECOG PS of zero at the time of treatment initiation were prognostically significant. Further investigation using this regimen including randomized comparisons, the incorporation of molecular data, and use of additional agents is merited.

7.
Cancer Gene Ther ; 30(8): 1066-1071, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37037906

RESUMEN

Ewing sarcoma (ES) is an aggressive malignant tumor, characterized by non-random chromosomal translocations that produce fusion genes. Fusion genes and fusion protein products are promising targets for gene therapy. Therapeutic approaches and strategies vary based on target molecules (nucleotides, proteins) of interest. We present an extensive literature review of active molecules for gene therapy and methods of gene therapy delivery, both of which are necessary for successful treatment.


Asunto(s)
Neoplasias Óseas , Sarcoma de Ewing , Humanos , Sarcoma de Ewing/genética , Sarcoma de Ewing/terapia , Sarcoma de Ewing/patología , Neoplasias Óseas/terapia , Proteínas , Terapia Genética , Proteínas de Fusión Oncogénica/genética
8.
Case Rep Oncol ; 16(1): 1353-1361, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37946745

RESUMEN

Introduction: Bing-Neel syndrome (BNS) is a rare and heterogenous manifestation of Waldenström macroglobulinemia (WM) involving central nervous system (CNS) infiltration by malignant lymphoplasmacytic cells. Efforts to standardize diagnostic criteria have improved in recent years, as have treatment options including the use of the Bruton tyrosine kinase inhibitor (BTKI) ibrutinib. Case Presentation: Here, we present the case of a 70-year-old male with a remote history of WM previously treated with bendamustine and rituximab, who presented to medical attention with several months of left-sided weakness, headache, and ataxia. Brain magnetic resonance imaging revealed numerous enhancing masses in the bilateral cerebral hemispheres, inferior medulla, and upper cervical spine. Laboratory studies showed serum IgM lambda monoclonal gammopathy and elevated free serum kappa and lambda light chains, while cerebrospinal fluid flow cytometry revealed CD19+ B cells. Stereotactic brain biopsy of a right frontal brain lesion was consistent with lymphoplasmacytic lymphoma, confirmed by a positive MYD88 L265P mutation. He received ibrutinib 420 mg orally daily, and this resulted in appreciable clinical and radiologic responses, which have persisted over a 31-month period. Conclusion: The advent of molecularly targeted agents and novel therapies for WM has provided patients and clinicians with additional therapeutic options. The use of BTK inhibitors with their high-level CNS penetrance, in particular, offers a novel way to treat BNS and improve patient overall survival while maintaining a high level of quality of life. We discuss the importance of MYD88 L265P testing in the context of BNS as well as the expanding role of BTKIs in treating this disease.

9.
Biomed Pharmacother ; 162: 114683, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37031493

RESUMEN

The balance between cell death and cell survival is a highly coordinated process by which cells break down and remove unnecessary or harmful materials in a controlled, highly regulated, and compartmentalized manner. Cell exposure to various stresses, such as oxygen starvation, a lack of nutrients, or exposure to radiation, can initiate autophagy. Autophagy is a carefully orchestrated process with multiple steps, each regulated by specific genes and proteins. Autophagy proteins impact cellular maintenance and cell fate in response to stress, and targeting this process is one of the most promising methods of anti-tumor therapy. It is currently not fully understood how autophagy affects different types of tumor cells, which makes it challenging to predict outcomes when this process is manipulated. In this review, we will explore the mechanisms of autophagy and investigate it as a potential and promising therapeutic target for aggressive sarcomas.


Asunto(s)
Sarcoma , Inanición , Humanos , Muerte Celular , Autofagia/fisiología , Apoptosis/genética
10.
Cancers (Basel) ; 15(21)2023 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-37958399

RESUMEN

Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.

11.
EMBO Mol Med ; 15(8): e17313, 2023 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-37491889

RESUMEN

Small-cell lung cancer (SCLC) is the most lethal type of lung cancer. Specifically, MYC-driven non-neuroendocrine SCLC is particularly resistant to standard therapies. Lurbinectedin was recently approved for the treatment of relapsed SCLC, but combinatorial approaches are needed to increase the depth and duration of responses to lurbinectedin. Using high-throughput screens, we found inhibitors of ataxia telangiectasia mutated and rad3 related (ATR) as the most effective agents for augmenting lurbinectedin efficacy. First-in-class ATR inhibitor berzosertib synergized with lurbinectedin in multiple SCLC cell lines, organoid, and in vivo models. Mechanistically, ATR inhibition abrogated S-phase arrest induced by lurbinectedin and forced cell cycle progression causing mitotic catastrophe and cell death. High CDKN1A/p21 expression was associated with decreased synergy due to G1 arrest, while increased levels of ERCC5/XPG were predictive of increased combination efficacy. Importantly, MYC-driven non-neuroendocrine tumors which are resistant to first-line therapies show reduced CDKN1A/p21 expression and increased ERCC5/XPG indicating they are primed for response to lurbinectedin-berzosertib combination. The combination is being assessed in a clinical trial NCT04802174.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Recurrencia Local de Neoplasia , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo
12.
JAMA Oncol ; 9(12): 1660-1668, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37824131

RESUMEN

Importance: Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. Objective: To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. Design, Setting, and Participants: This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Interventions: Two doses of IT GLA-SE (5 µg and 10 µg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Main Outcomes and Measures: Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Results: Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. Conclusions and Relevance: In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02180698.


Asunto(s)
Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Femenino , Anciano , Masculino , Receptor Toll-Like 4/agonistas , Linfocitos T , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/radioterapia , Sarcoma/tratamiento farmacológico , Sarcoma/radioterapia , Receptores de Antígenos de Linfocitos T
13.
JAMA Oncol ; 9(12): 1669-1677, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37824137

RESUMEN

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan. Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC. Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible. Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI. Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%]). Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.


Asunto(s)
Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Carcinoma Pulmonar de Células Pequeñas/patología , Topotecan/efectos adversos , Neoplasias Pulmonares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Recurrencia
14.
Clin Cancer Res ; 29(18): 3603-3611, 2023 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-37227187

RESUMEN

PURPOSE: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations. PATIENTS AND METHODS: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels. RESULTS: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer. CONCLUSIONS: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inmunoconjugados , Neoplasias Pulmonares , Masculino , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Camptotecina/efectos adversos , Camptotecina/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/administración & dosificación
15.
Clin Nucl Med ; 47(5): 409-413, 2022 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-35307721

RESUMEN

BACKGROUND: Peptide receptor radioligand therapy (PRRT) was Food and Drug Administration approved in 2018 for the treatment of unresectable somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs) and provides an important option for patients with advanced disease. A known adverse effect of this treatment is hematologic toxicity, although usually transient. We present 3 patients with metastatic gastroenteropancreatic NETs treated with PRRT who were evaluated for severe persistent thrombocytopenia. METHODS: Three patients who commenced therapy with PRRT were known to proceed to a bone marrow (BM) biopsy for persistent severe thrombocytopenia and were included in this study. These patients were identified retrospectively and evaluated for their tumor properties, including immunohistochemical markers, treatment modalities, and clinical outcomes. RESULTS: All 3 patients had metastatic NETs that progressed on prior lines of therapy and were treated with 1 to 4 doses of 177Lu-DOTATATE 7.4 GBq (200 mCi) before developing grade 3 (25,000 to 50,000/µL) refractory thrombocytopenia. All patients had concurrent bone metastases, and 2 of the 3 had baseline grade 1 thrombocytopenia. In all 3 cases, BM biopsy documented widespread tumor infiltration. CONCLUSIONS: Severe refractory thrombocytopenia after PRRT is rare and may result from numerous known causes, including radiation-induced myelotoxicity, myelodysplastic syndrome, and tumor BM infiltration. We present 3 cases of thrombocytopenia related to persistent or progressive BM metastasis. Although known bone metastasis is not a contraindication to PRRT, thrombocytopenia may be a manifestation of tumor progression and should be considered when making decisions about continuation of therapy.


Asunto(s)
Tumores Neuroendocrinos , Compuestos Organometálicos , Trombocitopenia , Humanos , Tumores Neuroendocrinos/complicaciones , Tumores Neuroendocrinos/radioterapia , Octreótido/uso terapéutico , Compuestos Organometálicos/efectos adversos , Tomografía de Emisión de Positrones , Cintigrafía , Receptores de Péptidos , Estudios Retrospectivos , Trombocitopenia/complicaciones
16.
Cancers (Basel) ; 14(8)2022 Apr 14.
Artículo en Inglés | MEDLINE | ID: mdl-35454895

RESUMEN

Ewing sarcoma (ES) is an uncommon cancer that arises in mesenchymal tissues and represents the second most widespread malignant bone neoplasm after osteosarcoma in children. Amplifications in genomic, proteomic, and metabolism are characteristics of sarcoma, and targeting altered cancer cell molecular processes has been proposed as the latest promising strategy to fight cancer. Recent technological advancements have elucidated some of the underlying oncogenic characteristics of Ewing sarcoma. Offering new insights into the physiological basis for this phenomenon, our current review examines the dynamics of ES signaling as it related to both ES and the microenvironment by integrating genomic and proteomic analyses. An extensive survey of the literature was performed to compile the findings. We have also highlighted recent and ongoing studies integrating metabolomics and genomics aimed at better understanding the complex interactions as to how ES adapts to changing biochemical changes within the tumor microenvironment.

17.
J Bone Oncol ; 35: 100440, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35855933

RESUMEN

Ewing's sarcoma (ES) is an aggressive malignant tumor commonly affecting adolescents. The standard of care includes surgical treatment and systemic therapies, although ES patients often develop drug resistance, leading to disease progression. Tumorigenesis in Ewing's sarcoma has unique characteristics that allow for the development of targeted therapeutics. New data on the role of oncogenic drivers in ES tumorigenesis, particularly in relation to treatment-induced stress, offers new therapeutic opportunities. This review summarizes the latest information on the clinically relevant oncogenes found in Ewing's sarcoma, their biological roles, and candidate targets for improving ES patient outcomes.

18.
Cancers (Basel) ; 14(5)2022 Mar 02.
Artículo en Inglés | MEDLINE | ID: mdl-35267598

RESUMEN

Patients with metastatic soft tissue sarcoma (STS) have a poor prognosis and few available systemic treatment options. Trabectedin is currently being investigated as a potential adjunct to immunotherapy as it has been previously shown to kill tumor-associated macrophages. In this retrospective study, we sought to identify biomarkers that would be relevant to trials combining trabectedin with immunotherapy. We performed a single-center retrospective study of sarcoma patients treated with trabectedin with long-term follow-up. Multiplex gene expression analysis using the NanoString platform was assessed, and an exploratory analysis using the lasso-penalized Cox regression and kernel association test for survival (MiRKAT-S) methods investigated tumor-associated immune cells and correlated their gene signatures to patient survival. In total, 147 sarcoma patients treated with trabectedin were analyzed, with a mean follow-up time of 5 years. Patients with fewer prior chemotherapy regimens were more likely to stay on trabectedin longer (pairwise correlation = -0.17, p = 0.04). At 5 years, increased PD-L1 expression corresponded to worse outcomes (HR = 1.87, p = 0.04, q = 0.199). Additionally, six immunologic gene signatures were associated with up to 7-year survival by MiRKAT-S, notably myeloid-derived suppressor cells (p = 0.023, q = 0.058) and M2 macrophages (p = 0.03, q = 0.058). We found that the number of chemotherapy regimens prior to trabectedin negatively correlated with the number of trabectedin cycles received, suggesting that patients may benefit from receiving trabectedin earlier in their therapy course. The correlation of trabectedin outcomes with immune cell infiltrates supports the hypothesis that trabectedin may function as an immune modulator and supports ongoing efforts to study trabectedin in combination with immunotherapy. Furthermore, tumors with an immunosuppressive microenvironment characterized by macrophage infiltration and high PD-L1 expression were less likely to benefit from trabectedin, which could guide clinicians in future treatment decisions.

19.
Mol Cancer Ther ; 21(6): 999-1009, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35405743

RESUMEN

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.


Asunto(s)
Receptores Quiméricos de Antígenos , Sarcoma , Animales , Antígenos B7 , Línea Celular Tumoral , Perros , Humanos , Sarcoma/tratamiento farmacológico , Linfocitos T , Ensayos Antitumor por Modelo de Xenoinjerto
20.
J Immunother Cancer ; 9(5)2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33963013

RESUMEN

BACKGROUND: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression. METHOD: We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15. RESULTS: Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers. CONCLUSIONS: ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression.


Asunto(s)
Antígenos de Neoplasias/inmunología , Proliferación Celular/efectos de los fármacos , Inmunoterapia Adoptiva , Interleucina-15/farmacología , Liposarcoma Mixoide/terapia , Activación de Linfocitos/efectos de los fármacos , Proteínas de la Membrana/inmunología , Células T de Memoria/efectos de los fármacos , Células T de Memoria/trasplante , Sarcoma Sinovial/terapia , Adulto , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Línea Celular Tumoral , Técnicas de Cocultivo , Ciclofosfamida/uso terapéutico , Citotoxicidad Inmunológica/efectos de los fármacos , Humanos , Memoria Inmunológica , Inmunoterapia Adoptiva/efectos adversos , Liposarcoma Mixoide/inmunología , Liposarcoma Mixoide/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Células T de Memoria/inmunología , Células T de Memoria/metabolismo , Persona de Mediana Edad , Agonistas Mieloablativos/uso terapéutico , Proyectos Piloto , Sarcoma Sinovial/inmunología , Sarcoma Sinovial/metabolismo , Factores de Tiempo , Acondicionamiento Pretrasplante , Resultado del Tratamiento , Microambiente Tumoral
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