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Journal For Immunotherapy of Cancer Jul 2023Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without...
Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial.
BACKGROUND
Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC.
PATIENTS AND METHODS
This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS).
RESULTS
Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7-24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%.
CONCLUSION
Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.
Topics: Humans; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Ipilimumab; Lung Neoplasms; Nivolumab; Radiosurgery; Combined Modality Therapy
PubMed: 37402581
DOI: 10.1136/jitc-2023-006871 -
JCI Insight Jun 2023The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the...
The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of lung cancer in mice, we show that PBT in tandem with an anti-PD1 antibody substantially reduced growth in both irradiated and unirradiated tumors. This was accompanied by robust activation of the immune response, as evidenced by whole-tumor and single-cell RNA sequencing showing upregulation of a multitude of immune-related transcripts. This response was further significantly enhanced by the injection of the tumor to be irradiated with NBTXR3 nanoparticles. Tumors of mice treated with the triple combination exhibited increased infiltration and activation of cytotoxic immune cells. This triple combination eradicated both tumors in 37.5% of the treated mice and showed robust long-term immunity to cancer.
Topics: Animals; Mice; Radioimmunotherapy; Protons; Lung Neoplasms; Immunotherapy; Nanoparticles
PubMed: 37345658
DOI: 10.1172/jci.insight.167749 -
Melanoma Research Aug 2023There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can...
There is no currently approved adoptive cellular therapy for solid tumors. Pre-clinical and clinical studies have demonstrated that low-dose radiotherapy (LDRT) can enhance intratumoral T cell infiltration and efficacy. This case report describes a 71-year-old female patient with rectal mucosal melanoma that had developed metastases to liver, lung, mediastinum, axillary nodes, and brain. After systemic therapies had failed, she enrolled in the radiation sub-study of our phase-I clinical trial exploring the safety and efficacy of afamitresgene autoleucel (afami-cel), genetically engineered T cells with a T cell receptor (TCR) targeting the MAGE-A4 tumor antigen in patients with advanced malignancies (NCT03132922). Prior to the infusion of afami-cel, she received concurrent lymphodepleting chemotherapy and LDRT at 5.6 Gy/4 fractions to the liver. Time to partial response was 10 weeks, and duration of overall response was 18.4 weeks. Although the patient progressed at 28 weeks, the disease was well controlled after high-dose radiotherapy to liver metastases and checkpoint inhibitors. As of the last follow-up, she remains alive over two years after LDRT and afami-cel therapy. This report suggests that afami-cel in combination with LDRT safely enhanced clinical benefit. This provides evidence for further exploring the benefit of LDRT in TCR-T cell therapy.
Topics: Female; Humans; Aged; Melanoma; HLA-A2 Antigen; Immunotherapy, Adoptive; Skin Neoplasms; Receptors, Antigen, T-Cell; Cell- and Tissue-Based Therapy
PubMed: 37325860
DOI: 10.1097/CMR.0000000000000869 -
Cancer Immunology, Immunotherapy : CII Sep 2023Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3...
Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.
Topics: Mice; Animals; NLR Family, Pyrin Domain-Containing 3 Protein; Inflammasomes; Antigen Presentation; Cytokines; Adenocarcinoma of Lung
PubMed: 37289257
DOI: 10.1007/s00262-023-03471-x -
Microbiology Spectrum Jun 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 propagation is mediated by the...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 propagation is mediated by the protein interaction between viral proteins and host cells. Tyrosine kinase has been implicated in viral replication, and hence, it has become a target for developing antiviral drugs. We have previously reported that receptor tyrosine kinase inhibitor blocks the replication of hepatitis C virus (HCV). In the present study, we investigated two receptor tyrosine kinase-specific inhibitors, amuvatinib and imatinib, for their potential antiviral efficacies against SARS-CoV-2. Treatment with either amuvatinib or imatinib displays an effective inhibitory activity against SARS-CoV-2 propagation without an obvious cytopathic effect in Vero E6 cells. Notably, amuvatinib exerts a stronger antiviral activity than imatinib against SARS-CoV-2 infection. Amuvatinib blocks SARS-CoV-2 infection with a 50% effective concentration (EC) value ranging from ~0.36 to 0.45 μM in Vero E6 cells. We further demonstrate that amuvatinib inhibits SARS-CoV-2 propagation in human lung Calu-3 cells. Using pseudoparticle infection assay, we verify that amuvatinib blocks SARS-CoV-2 at the entry step of the viral life cycle. More specifically, amuvatinib inhibits SARS-CoV-2 infection at the binding-attachment step. Moreover, amuvatinib exhibits highly efficient antiviral activity against emerging SARS-CoV-2 variants. Importantly, we demonstrate that amuvatinib inhibits SARS-CoV-2 infection by blocking ACE2 cleavage. Taken together, our data suggest that amuvatinib may provide a potential therapeutic agent for the treatment of COVID-19. Tyrosine kinase has been implicated in viral replication and has become an antiviral drug target. Here, we chose two well-known receptor tyrosine kinase inhibitors, amuvatinib and imatinib, and evaluated their drug potencies against SARS-CoV-2. Surprisingly, amuvatinib displays a stronger antiviral activity than imatinib against SARS-CoV-2. Amuvatinib blocks SARS-CoV-2 infection by inhibiting ACE2 cleavage and the subsequent soluble ACE2 receptor. All these data suggest that amuvatinib may be a potential therapeutic agent in SARS-CoV-2 prevention for those experiencing vaccine breakthroughs.
Topics: Animals; Humans; COVID-19; SARS-CoV-2; Imatinib Mesylate; Angiotensin-Converting Enzyme 2; Antiviral Agents; Protein-Tyrosine Kinases; Life Cycle Stages
PubMed: 36995225
DOI: 10.1128/spectrum.05105-22 -
Frontiers in Immunology 2022CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense... (Meta-Analysis)
Meta-Analysis
CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.
Topics: Humans; Protein Binding; Antibodies, Monoclonal; Fatigue; Headache; Neoplasms; CD47 Antigen
PubMed: 36439116
DOI: 10.3389/fimmu.2022.1027235 -
Frontiers in Immunology 2022The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune...
The efficacy of immunoradiotherapy consisting of radiation therapy and immune checkpoint blockade relies on effectively promoting the systemic antitumor immune response's activation while simultaneously reducing local factors favoring immune suppression. We previously demonstrated that NBTXR3, a nanoparticle radioenhancer, significantly improved immune responses in a murine anti-PD1-resistant metastatic lung cancer model. We hypothesize that radioactivated-NBTXR3 addition to anti-PD1 and a second-generation anti-CTLA4 could improve treatment effectiveness. To test this hypothesis, we inoculated mice with 344SQR cells in the right and left legs to establish primary and secondary tumors. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by three fractions of 12 Gy radiation on days 8, 9, and 10. The secondary tumors received two fractions of 1Gy radiation on days 13 and 14. Multiple rounds of anti-PD1, anti-CTLA4 or nonfucosylated anti-CTLA4 were given to the mice. Immune profiling of the tumors revealed that the combination of NBTXR3 with immunoradiotherapy significantly upregulated the activities of a wide range of antitumor immune pathways and reduced the abundance of regulatory suppressor T cells. This combination effectively eradicated the primary and secondary tumors and increased animal survival to 75%. Remarkably, previously treated with NBTXR3-containing treatment, the survivor mice exhibited a long-lasting antitumor memory immune response. This data provides compelling evidence of the efficacy of NBTXR3 to synergize with the immunoradiotherapy approach when combined with an anti-PD1 and multiple checkpoints such as a second generation anti-CTLA4 and show the potential for clinical uses of antitumor immunomodulatory effects of NBTXR3.
Topics: Animals; Mice; Radioimmunotherapy; Programmed Cell Death 1 Receptor; Lung Neoplasms; Immunotherapy; Antineoplastic Agents
PubMed: 36405757
DOI: 10.3389/fimmu.2022.1022011 -
Frontiers in Immunology 2022Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used...
Radiation therapy (XRT) has a well-established role in cancer treatment. Given the encouraging results on immunostimulatory effects, radiation has been increasingly used with immune-check-point inhibitors in metastatic disease, especially when immunotherapy fails due to tumor immune evasion. We hypothesized that using high-dose stereotactic radiation in cycles (pulses) would increase T-cell priming and repertoire with each pulse and build immune memory in an incremental manner. To prove this hypothesis, we studied the combination of anti-CTLA-4 and Pulsed radiation therapy in our 344SQ non-small cell lung adenocarcinoma murine model. Primary and secondary tumors were bilaterally implanted in 129Sv/Ev mice. In the Pulsed XRT group, both primary and secondary tumors received 12Gyx2 radiation one week apart, and blood was collected seven days afterwards for TCR repertoire analysis. As for the delayed-Pulse group, primary tumors received 12Gyx2, and after a window of two weeks, the secondary tumors received 12Gyx2. Blood was collected seven days after the second cycle of radiation. The immunotherapy backbone for both groups was anti-CTLA-4 antibody to help with priming. Treatment with Pulsed XRT + anti-CTLA-4 led to significantly improved survival and resulted in a delayed tumor growth, where we observed enhanced antitumor efficacy at primary tumor sites beyond XRT + anti-CTLA-4 treatment group. More importantly, Pulsed XRT treatment led to increased CD4 effector memory compared to single-cycle XRT. Pulsed XRT demonstrated superior efficacy to XRT in driving antitumor effects that were largely dependent on CD4 T cells and partially dependent on CD8 T cells. These results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and sustained antitumor response.
Topics: Mice; Animals; Tumor Burden; CD8-Positive T-Lymphocytes; Immunologic Memory; Immunotherapy; Adenocarcinoma; Receptors, Antigen, T-Cell
PubMed: 36275767
DOI: 10.3389/fimmu.2022.984318 -
Journal of Nanobiotechnology Sep 2022While improvements in immunoradiotherapy have significantly improved outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at...
BACKGROUND
While improvements in immunoradiotherapy have significantly improved outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to immunoradiotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of immunoradiotherapy.
METHODS
We combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors: PD1, LAG3, and TIGIT, and tested the treatment efficacy in an anti-PD1-resistant lung cancer model in mice. 129 Sv/Ev mice were inoculated with fifty thousand αPD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected into the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 µg), αLAG3 (200 µg), and αTIGIT (200 µg) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42.
RESULTS
This nanoparticle-mediated combination therapy is effective at controlling the growth of irradiated and distant unirradiated tumors, enhancing animal survival, and is the only one that led to the destruction of both tumors in approximately 30% of the treated mice. Corresponding with this improved response is robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment.
CONCLUSION
Our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune checkpoint receptors and provide a pre-clinical rationale for investigating its translation into human patients.
Topics: Animals; Antigens, CD; Antineoplastic Agents; Humans; Lung Neoplasms; Mice; Nanoparticles; Radioimmunotherapy; Receptors, Immunologic; Treatment Outcome; Lymphocyte Activation Gene 3 Protein
PubMed: 36123677
DOI: 10.1186/s12951-022-01621-4 -
Vaccines Aug 2022The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the...
The pandemic of SARS-CoV-2 infections is a severe threat to human life and the world economic condition. Although vaccination has reduced the outspread, but still the situation is not under control because of the instability of RNA sequence patterns of SARS-CoV-2, which requires effective drugs. Several studies have suggested that the SARS-CoV-2 infection causing hub differentially expressed genes (Hub-DEGs). However, we observed that there was not any common hub gene (Hub-DEGs) in our analyses. Therefore, it may be difficult to take a common treatment plan against SARS-CoV-2 infections globally. The goal of this study was to examine if more representative Hub-DEGs from published studies by means of hub of Hub-DEGs (hHub-DEGs) and associated potential candidate drugs. In this study, we reviewed 41 articles on transcriptomic data analysis of SARS-CoV-2 and found 370 unique hub genes or studied genes in total. Then, we selected 14 more representative Hub-DEGs (, , , , , , , , , , , , , ) as hHub-DEGs by their protein-protein interaction analysis. Their associated biological functional processes, transcriptional, and post-transcriptional regulatory factors. Then we detected hHub-DEGs guided top-ranked nine candidate drug agents (Digoxin, Avermectin, Simeprevir, Nelfinavir Mesylate, Proscillaridin, Linifanib, Withaferin, Amuvatinib, Atazanavir) by molecular docking and cross-validation for treatment of SARS-CoV-2 infections. Therefore, the findings of this study could be useful in formulating a common treatment plan against SARS-CoV-2 infections globally.
PubMed: 36016137
DOI: 10.3390/vaccines10081248