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Diverse Resistance Mechanisms to the Third-Generation ALK Inhibitor Lorlatinib in ALK-Rearranged Lung Cancer

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (1)

Purpose: Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor with proven efficacy in patients with ALK-rearranged lung cancer previously treated with first- and second-generation ALK inhibitors. Beside compound mutations in the ALK kinase domain, other resistance mechanisms driving lorlatinib resistance remain unknown. We aimed to characterize the mechanisms of resistance to lorlatinib occurring in patients with ALK-rearranged lung cancer and design new therapeutic strategies in this setting. Experimental Design: Resistance mechanisms were investigated in 5 patients resistant to lorlatinib. Longitudinal tumor biopsies were studied using high-throughput next-generation sequencing. Patient-derived models were developed to characterize the acquired resistance mechanisms, and Ba/F3 cell mutants were generated to study the effect of novel ALK compound mutations. Drug combinatory strategies were evaluated in vitro and in vivo to overcome lorlatinib resistance. Results: Diverse biological mechanisms leading to lorlatinib resistance were identified. Epithelial-mesenchymal transition (EMT) mediated resistance in two patient-derived cell lines and was susceptible to dual SRC and ALK inhibition. We characterized three ALK kinase domain compound mutations occurring in patients, L1196M/D1203N, F1174L/G1202R, and C1156Y/G1269A, with differential susceptibility to ALK inhibition by lorlatinib. We identified a novel bypass mechanism of resistance caused by NF2 loss-of-function mutations, conferring sensitivity to treatment with mTOR inhibitors. Conclusions: This study shows that mechanisms of resistance to lorlatinib are diverse and complex, requiring new therapeutic strategies to tailor treatment upon disease progression.

A Virus-Infected, Reprogrammed Somatic Cell-Derived Tumor Cell (VIReST) Vaccination Regime Can Prevent Initiation and Progression of Pancreatic Cancer

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (2)

Purpose: Pancreatic cancer remains one of the most lethal cancers, and late detection renders most tumors refractory to conventional therapies. Development of cancer prophylaxis may be the most realistic option for improving mortality associated with this disease, Here, we develop a novel individualized prophylactic and therapeutic vaccination regimen using induced pluripotent stem cells (iPSC), gene editing, and tumor-targeted replicating oncolytic viruses. Experimental Design: We created a Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime. iPSCs from healthy cells were induced to pancreatic tumor cells using in situ gene editing via stable provision of KRas(G12D) and p53(R172H) tumor driver mutations. These cells were preinfected with oncolytic Adenovirus (AdV) as prime or Vaccinia virus (VV) as boost, to improve vaccine immunogenicity, prior to delivery of vaccines in a sequential regime to young KPC transgenic mice, genetically programmed to develop pancreatic cancer, to prevent and delay disease development. Results: Tumor cells preinfected with oncolytic AdV as prime or VV as boost were the best regime to induce tumor-specific immunity, iPSC-derived tumor cells were highly related in antigen repertoire to pancreatic cancer cells of KPC transgenic mice, suggesting that an individual's stem cells can provide an antigenically matched whole tumor cell vaccine. The VIReST vaccination primed tumor-specific T-cell responses, resulting in delayed disease emergence and progression and significantly prolonged survival of KPC transgenic mice. Importantly, this regime was well-tolerated and nontoxic. Conclusions: These results provide both proof of concept and a robust technology platform for the development of personalized prophylactic cancer vaccines to prevent pancreatic malignancies in at-risk individuals.

Submucosal Saline Injection Followed by Endoscopic Ultrasound versus Endoscopic Ultrasound Only for Distinguishing between T1a and T1b Esophageal Cancer

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (2)

Purpose: To examine whether submucosal saline injection (SSI) can improve traditional endoscopic ultrasound (EUS) accuracy in distinguishing between T1a and T1b stage esophageal squamous cell carcinoma (ESCC). Experimental Design: Patients with TINOM0 stage ESCC (n =180) ages 18 to 85 years were enrolled between February 14, 2012 to June 4, 2018 at Sun Yat-sen University Cancer Center (Guangdong, China). were randomly assigned (1:1) to receive either EUS examination after 3-5 mL SSI or EUS only examination. All the patients were referred to thoracic surgeons to receive endoscopic resection (ER) or esophagectomy 5 to 10 days after EUS examination. Standard EUS criteria were used to preoperatively stage the ESCC cases, and surgical pathology reports after referral were used to postoperatively stage the cases, The primary endpoint was the diagnostic accuracy of T1b staging [defined as the sum of the true positive (T1b) and true negative (T1a) cases divided by the total number of cases]. Results: Among the per-protocol population, the SSI+EUS group (n 81) was superior to the EUS-only group (n = 85) in terms of the diagnostic accuracy for Tlb staging [93.8% (95% confidence interval (CI), 88.6-99.1) vs. 65.9% (95% CI, 55.8-76.0); P < 0.0011. The positive predictive value of SSI+EUS for diagnosing Ti b ESCC reached 90.9% (95% CI, 81.1-100), which was significantly superior to that of EUS only [0.576 (0.450-0.702), P = 0.001]. Conclusions: SSI significantly improves the diagnostic accuracy of EUS in distinguishing between T1a and T1b ESCC, which might help avoid unnecessary esophagectomy and diagnostic ER.

Whole-Slide Image Analysis Reveals Quantitative Landscape of Tumor-Immune Microenvironment in Colorectal Cancers

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (4)

Purpose: Despite the well-known prognostic value of the tumor-immune microenvironment (TIME) in colorectal cancers, objective and readily applicable methods for quantifying tumor-infiltrating lymphocytes (TIL) and the tumor-stroma ratio (TSR) are not yet available. Experimental Design: We established an open-source software-based analytic pipeline for quantifying TILs and the TSR from whole-slide images obtained after CD3 and CD8 IHC staining. Using a random forest classifier, the method separately quantified intraepithelial TILs (iTIL) and stromal TILs (sTIL). We applied this method to discovery and validation cohorts of 578 and 283 stage III or high-risk stage II colorectal cancers patients, respectively, who were subjected to curative surgical resection and oxlaliplatin-based adjuvant chemotherapy. Results: Automatic quantification of iTILs and sTILs showed a moderate concordance with that obtained after visual inspection by a pathologist. The K-means-based consensus clustering of 197 TIME parameters that showed robustness against interobserver variations caused colorectal cancers to be grouped into five distinctive subgroups, reminiscent of those for consensus molecular subtypes (CMS1-4 and mixed/intermediate group). In accordance with the original CMS report, the CMS4-like subgroup (cluster 4) was significantly associated with a worse 5-year relapse-free survival and proved to be an independent prognostic factor. The clinicopathologic and prognostic features of the TIME subgroups have been validated in an independent validation cohort. Conclusions: Machine-learning-based image analysis can be useful for extracting quantitative information about the TIME, using whole-slide histopathologic images. This information can classify colorectal cancers into clinicopathologically relevant subgroups without performing a molecular analysis of the tumors.

Clinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (24)

Purpose Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkcrs. Experimental Design: We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes. Results: In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures (hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P =0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germ line rare variants are more likely to have poor OS and progression-free survival. Conclusions: Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.

Activity and Safety of Geptanolimab (GB226) for Patients with Unresectable, Recurrent, or Metastatic Alveolar Soft Part Sarcoma: A Phase II, Single-arm Study

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (24)

Purpose: Patients with alveolar soft part sarcoma (ASPS) are rare and have few treatment options. We assessed the activity of geptanolimab (GB226), a fully humanized programmed cell death protein 1 antibody, for patients with unresectable, recurrent, or metastatic ASPS. Patients and Methods: We conducted this multicenter, single-arm, phase II study (Gxplore-005, NCT03623581) in patients aged 18-75 years who had unresectable, recurrent, or metastatic ASPS at 11 sites in China. Patients received intravenous geptanolimab (3 mg/kg) every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate assessed by independent review committee (IRC) per RECIST 1.1 in the full analysis set population. Results: Between September 6, 2018 and March 6, 2019, we enrolled and treated 37 patients with 23 (62.2%) having received prior systemic treatment. Fourteen [37.8%; 95% confidence interval (CI), 22.5-55.2] of 37 patients had an objective response assessed by IRC with a 6-month duration of response rate of 91.7%. Median progression-free survival was 6.9 months (95% CI, 5.0-not reached) and disease control was achieved in 32 (86.5%; 95% CI, 71.2-95.5) patients. Three of 37 patients reported grade 3 treatment-related adverse events (TRAEs), including anemia, hypophysitis, and proteinuria [one each (2.7%)]. No grade 4 TRAEs were observed. Two (5.4%) patients discontinued treatment due to TRAEs (one with hypophysitis and one with Mobitz type I atrioventricular block). The baseline percentage of CD4(+) T cells was adversely associated with patient response (P = 0.031). Conclusions: Geptanolimab has clinically meaningful activity and a manageable safety profile in unresectable, recurrent, or metastatic ASPS.

Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (6)

Purpose: Emerging evidence indicates that castration-resistant prostate cancer (CRPC) is often driven by constitutively active androgen receptor (AR) or its V7 splice variant (AR-V7) and commonly becomes resistant to endocrine therapy. The aim of this work is to evaluate the function of a kinesin protein, KIF4A, in regulating AR/AR-V7 in prostate cancer endocrine therapy resistance. Experimental Design: We examined KIF4A expression in clinical prostate cancer specimens by IHC. Regulated pathways were investigated by qRT-PCR, immunoblot analysis, immunoprecipitation, and luciferase reporter and chromatin immunoprecipitation (ChIP) assays. A series of functional analyses were conducted in cell lines and xenograft models. Results: Examination of the KIF4A protein and mRNA levels in patients with prostate cancer showed that increased expression of KIF4A was positively correlated with androgen receptor (AR) levels. Patients with lower tumor KIF4A expression had improved overall survival and disease-free survival. Mechanistically, KIF4A and AR form an auto-regulatory positive feedback loop in prostate cancer: KIF4A binds AR and AR-V7 and prevents CHIP-mediated AR and AR-V7 degradation; AR binds the promoter region of KIF4A and activates its transcription. KIF4A promotes castration-sensitive and castration-resistant prostate cancer cell growth through AR-and AR-V7-dependent signaling. Furthermore, KIF4A expression is upregulated in enzalutamide-resistant prostate cancer cells, and KIF4A knockdown effectively reverses enzalutamide resistance and enhances the sensitivity of CRPC cells to endocrine therapy. Conclusions: These findings indicate that KIF4A plays an important role in the progression of CRPC and serves as a crucial determinant of the resistance of CRPC to endocrine therapy.

Characterization of Immune Dysfunction and Identification of Prognostic Immune-Related Risk Factors in Acute Myeloid Leukemia

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (7)

Purpose: This study aims to provide comprehensive insights into longitudinal immune landscape in acute myeloid leukemia (AML) development and treatment, which may contribute to predict prognosis and guide clinical decisions. Experimental Design: Periphery blood samples from 79 patients with AML (at diagnosis or/and after chemotherapy or at relapse) and 24 healthy controls were prospectively collected. We performed phenotypic and functional analysis of various lymphocytes through multiparametric flow cytometry and investigated prognostic immune-related risk factors. Results: Immune defects in AML were reflected in T and natural killer (NK) cells, whereas B-cell function remained unaffected. Both CD8(+) T and CD4(+) T cells exhibited features of senescence and exhaustion at diagnosis. NK dysfunction was supported by excessive maturation and downregulation of NKG2D and NKP30. Diseased gamma delta T cells demonstrated a highly activated or even exhausted state through PD-1 upregulation and NKG2D downregulation. Effective therapeutic response following chemotherapy correlated with T and NK function restoration. Refractory and relapsed patients demonstrated even worse immune impairments, and selective immune signatures apparently correlated clinical outcomes and survival. PD-1 expression in CD8(+) T cells was independently predictive of poor overall survival and event-free survival. Conclusions: T-cell senescence and exhaustion, together with impaired NK and gamma delta T-cell function, are dominant aspects involved in immune dysfunction in AML. Noninvasive immune testing of blood samples could be applied to predict therapeutic reactivity, high risk for relapse, and unfavorable prognosis.

Smoothened Promotes Glioblastoma Radiation Resistance Via Activating USP3-Mediated Claspin Deubiquitination

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (7)

Purpose: Glioblastoma (GBM) is one of the most aggressive and lethal cancer types in humans. The standard treatment approach is surgery followed by chemoradiation. However, the molecular mechanisms of innate tumor radioresistance remain poorly understood. Experimental Design: We tested the expression of Smoothened (Smo) in primary and recurrent GBM tissues and cells. Then, we determined radiation effectiveness against primary and recurrent GBM cells. Lastly, the functional role of Smo in GBM radioresistance was further confirmed by in vitro and in vivo experiments. Results: We reported that Smo was significantly upregulated in recurrent GBM cell lines and tumor tissues following radiation treatment. Higher Smo expression indicated poor prognosis of GBM patients after radiation treatment. Smo had radioresistance effects in both GBM cells and human tumor xenografts. The mechanisms underlying these effects involved the attenuation of DNA damage repair caused by IR. Importantly, we found that the effect of Smo on radioresistance was mediated by Claspin poly-ubiquitination and proteasomal degradation, leading to the regulation of ATR-Chk1 signaling. Moreover, we found that Smo reduced Claspin polyubiquitination and proteasomal degradation by promoting USP3 transcription. Furthermore, we demonstrated that the Smo inhibitor GDC-0449 induced radiosensitivity to GBM. Conclusions: These data suggest that Smo confers radiation resistance in GBM by promoting USP3 transcription, leading to the activation of Claspin-dependent ATR-Chk1 signaling. These findings identify a potential mechanism of GBM resistance to radiation and suggest a potential therapeutic target for radiation resistance in GBM.

Sustained Therapeutic Efficacy of Humanized Anti-CD19 Chimeric Antigen Receptor T Cells in Relapsed/Refractory Acute Lymphoblastic Leukemia

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (7)

Purpose: Immunogenicity derived from the murine scFv, a major molecular compomemt of chimeric antigen receptors (CARs), may limit the persistence of CAR T cells, resulting in tumor relapse of patients in complete remission (CR). In this study, we developed a humanized anti-CD19 scFv CAR-T (hCAR-T) to treat patients with relapsed/refractory acute lymphoblastic leukemia (r/r ALL). Patients and Methods: In this one-arm, open-labeled study, we infused the T cells modified with hCAR to patients with r/r ALL. Patients were evaluated with long-term follow-up for response and safety of the treatment. The study was registered at Clinicaltrials.gov (NCT02349698). Results: Ten patients with r/r ALL were recruited for this study. All were response evaluable and all achieved CR; eight patients remained CR, and six were in CR for over 18 months without further treatment. A long-term persistence of hCAR T cells was observed in most of the patients. Among these patients, four of them with high tumor burden and rapidly progressive disease (median, 58%) experienced grade 3-4 cytokine release syndrome (CRS) and neurotoxicity. These severe CRSs were successfully controlled by tocilizumab, glucocorticoid, and plasma exchange. Conclusions: T cells expressing the humanized anti-CD19 scFv CARs exhibited sustained therapeutic efficacy in the treatment of r/r ALL. Low replase rate was associated with the long-term persistence of CAR T cells.

Efficacy, Safety, and Biomarkers of Toripalimab in Patients with Recurrent or Metastatic Neuroendocrine Neoplasms: A Multiple-Center Phase Ib Trial

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (10)

Purpose: Patients with recurrent or metastatic neuroendocrine neoplasms (NEN) had a poor prognosis and few treatment options. Toripalimab, a humanized IgG4 antibody specific for human PD-1 receptor, was first approved to treat second-line metastatic melanoma in China in 2018. Patients and Methods: The multiple-center phase Ib trial enrolled patients with NENs (Ki-67 >= 10%) after failure of first-line therapy received 3 mg/kg toripalimab once every two weeks. The primary objective was objective response rate (ORR) and safety. PD-L1 expression and whole-exome sequencing were performed on tumor biopsies. Secondary objectives included duration of response (DOR), disease control rate (DCR), and progression-free survival and overall survival. Results: Of 40 patients included from April 2017 to December 2018, 8 partial responses and 6 stable diseases were observed, for a 20% ORR and a 35% DCR. The median DOR was 15.2 months. Patients with PD-L1 expression (>= 10%) or high tumormutational burden (TMB) had better ORR than PD-L1 <10% (50.0% vs. 10.7%, P = 0.019) and TMB-low patients (75.0% vs. 16.1%, P = 0.03). Three of 8 (37.5%) responders harbored ARID1A mutations, whereas only 1 of 27 nonresponders had mutations (P = 0.03). Of note, 1 exceptional responder with TMB-L, microsatellite stable (MSS), and PD-L1-negative had multiple genomic arrangements with high prediction score for neoantigens. Conclusions: Toripalimab had antitumor activity and safety in treating recurrent or metastatic NENs. Patients with positive PD-L1 expression, TMB-H (top 10%), and/ormicrosatellite instable (MSI-H) might preferentially benefit from the treatment. The genomic mutation of ARID1A and high genomic rearrangements might be correlated with clinical benefit.

Biomarkers of Osimertinib Response in Patients with Refractory, EGFR-T790M-positive Non-Small Cell Lung Cancer and Central Nervous System Metastases: The APOLLO Study

期刊: CLINICAL CANCER RESEARCH, 2020; 26 (23)

Purpose: Dynamic biomarker monitoring may inform pathways for treating EGFR-T790M-positive non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases with osimertinib. This study aimed to determine the efficacy and safety of osimertinib for real-world patients with EGFR-T790M NSCLC and CNS metastases and to explore potential circulating biomarkers of therapeutic response. Patients and Methods: APOLLO (ClinicalTrials.gov registration: NCT02972333) was a prospective, single-arm, open-label trial which ran from January 2017 to April 2019. Eligible patients had confirmed EGFR-T790M-positive NSCLC, prior treatment with an EGFR-tyrosine kinase inhibitor, and CNS metastases. All enrolled patients received oral osimertinib 80 mg once daily until disease progression or intolerable toxicity. Primary outcome was overall progression-free survival (PFSo) and secondary outcomes included objective response rate (ORR) and adverse events (AE). Exploratory biomarker analysis involved collection of plasma and cerebrospinal fluid (CSF) samples for next-generation sequencing and drug penetration analysis. Results: From January to September 2017, 38 patients were enrolled. After a median follow-up of 8.2 months (range, 0.07-15.6), 23 (60.5%) of 38 patients had disease progression or death. Median PFSo was 8.4 months [95% confidence interval (CI), 5.8-10.9]. Overall ORR was 39.4%. Twelve (31.6%) of 38 patients had >= 1 grade 3-4 AE. Median osimertinib CSF penetration rate was 31.7%. Patients with undetectable plasma EGFR mutations at week 6 had improved PFSo compared with those with detectable mutations (not reached vs. 4.5 months; 95% CI, 0.0-1.1; P < 0.05). Conclusions: Osimertinib had potent activity against EGFRT-790M-positive NSCLC with CNS metastases. Dynamic monitoring of plasma EGFR may suffice for predicting clinical responses, mitigating the need for repeat CSF biopsy.

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