Patients with non–small-cell lung cancer were randomly assigned to three cycles of chemotherapy with or without nivolumab, an anti–PD-1 antibody. Event-free survival was longer with nivolumab than ...without it (31.6 months vs. 20.8 months), and the percentage of patients with a pathological complete response was 24.0% and 2.2%, respectively.
Anti-tumor electrochemotherapy, which consists in increasing anti-cancer drug uptake by means of electroporation, is now implanted in about 140 cancer treatment centers in Europe. Its use is ...supported by the English National Institute for Health and Care Excellence for the palliative treatment of skin metastases, and about 13,000 cancer patients were treated by this technology by the end of 2015. Efforts are now focused on turning this local anti-tumor treatment into a systemic one. Electrogenetherapy, that is the electroporation-mediated transfer of therapeutic genes, is currently under clinical evaluation and has brought excitement to enlarge the anti-cancer armamentarium. Among the promising electrogenetherapy strategies, DNA vaccination and cytokine-based immunotherapy aim at stimulating anti-tumor immunity. We review here the interests and state of development of both electrochemotherapy and electrogenetherapy. We then emphasize the potent beneficial outcome of the combination of electrochemotherapy with immunotherapy, such as immune checkpoint inhibitors or strategies based on electrogenetherapy, to simultaneously achieve excellent local debulking anti-tumor responses and systemic anti-metastatic effects.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer stem cells (CSC) have raised great excitement during the last decade and are promising targets for an efficient treatment of tumors without relapses and metastases. Among the various methods ...that enable to enrich cancer cell lines in CSC, tumorspheres culture has been predominantly used. In this report, we attempted to generate tumorspheres from several murine and human cancer cell lines: B16-F10, HT-29, MCF-7 and MDA-MB-231 cells. Tumorspheres were obtained with variable efficiencies from all cell lines except from MDA-MB-231 cells. Then, we studied several CSC characteristics in both tumorspheres and adherent cultures of the B16-F10, HT-29 and MCF-7 cells. Unexpectedly, tumorspheres-forming cells were less clonogenic and, in the case of B16-F10, less proliferative than attached cells. In addition, we did not observe any enrichment in the population expressing CSC surface markers in tumorspheres from B16-F10 (CD133, CD44 and CD24 markers) or MCF-7 (CD44 and CD24 markers) cells. On the contrary, tumorspheres culture of HT-29 cells appeared to enrich in cells expressing colon CSC markers, i.e. CD133 and CD44 proteins. For the B16-F10 cell line, when 1 000 cells were injected in syngenic C57BL/6 mice, tumorspheres-forming cells displayed a significantly lower tumorigenic potential than adherent cells. Finally, tumorspheres culture of B16-F10 cells induced a down-regulation of vimentin which could explain, at least partially, the lower tumorigenicity of tumorspheres-forming cells. All these results, along with the literature, indicate that tumorspheres culture of cancer cell lines can induce an enrichment in CSC but in a cell line-dependent manner. In conclusion, extensive characterization of CSC properties in tumorspheres derived from any cancer cell line or cancer tissue must be performed in order to ensure that the generated tumorspheres are actually enriched in CSC.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Electrochemotherapy (ECT) is a local cancer treatment that has been used over the course of more than 2 decades for the removal of cutaneous and subcutaneous tumors. Several lines of evidence support ...the premise that the immune system is an important factor underlying anticancer treatment efficacy, potentially including patient responses to ECT. The concept of immunogenic cell death (ICD) arose a few years ago, stating that some cancer treatments generate danger-associated molecular patterns (DAMPs) that trigger an adaptive immune response against tumors. Hence, dying cancer cells behave as a therapeutic vaccine, eliciting a cytotoxic immune response against surviving malignant cells. In our study, we sought to evaluate the ability of ECT to generate cancer cell death encompassing the immunostimulatory characteristics of ICD. To this end, we assayed CT26 murine colon cancer cells in vitro in response to either electric pulses (EPs) application only or in combination with the anticancer drug bleomycin (that is ECT) by quantification of calreticulin (CRT) membrane externalization, as well as the liberation of adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) protein. We show here that cell permeabilizing yet non-lethal electric pulses induce CRT exposure on the cell surface of EP-only treated cancer cells, as well as ATP release. However, the association of electric pulses along with the chemotherapeutic agent bleomycin was mandatory for HMGB1 release coincident with regimen-induced cell death. These data obtained in vitro were then substantiated by vaccination protocols performed in immunocompetent mice, showing that the injection of dying ECT-treated cells elicits an antitumor immune response that prevents the growth of a subsequent administration of viable cancer cells. We also confirmed previous results showing ECT treatment is much more efficient in immunocompetent animals than in immunodeficient ones, causing complete regressions in the former but not in the latter. This supports a central role for immunity in this beneficial outcome. In conclusion, we show that ECT not only possesses an intrinsic cytotoxic property toward cancer cells but also generates a systemic anticancer immune response via the activation of ICD. Hence, ECT may represent an interesting approach to treat solid tumors while preventing recurrence and metastasis, possibly in combination with immunostimulating agents.
In this article, we summarize results from the ongoing phase 3 CheckMate 816 clinical study that were published in
in 2022. The goal of CheckMate 816 was to find out if
, an immunotherapy that ...activates a person's immune system (the body's natural defense system) to fight cancer,
works better than
when given before surgery in people with non-small-cell lung cancer (NSCLC) that can be removed surgically (resectable NSCLC).
Adults who had not previously taken medications to treat NSCLC and whose cancer could be removed with surgery were included in CheckMate 816. During this study, a computer randomly assigned the treatment each person would receive before surgery for NSCLC. In total, 179 people were randomly assigned to receive
, and 179 people were randomly assigned to receive
. The researchers assessed whether people who received
lived longer without the cancer geting worse or coming back and whether there were any cancer cells left in the tumor and lymph nodes removed by surgery. The researchers also assessed how adding nivolumab to chemotherapy affected the timing and outcomes of surgery and whether the combination of these drugs was safe.
Researchers found that people who
lived longer without the cancer getting worse or coming back compared with those who took
. More people in the
group had no cancer cells left in the tumor and lymph nodes removed by surgery. Most people went on to have surgery in both treatment groups; the people who took
instead of
had less extensive surgeries and were more likely to have good outcomes after less extensive surgeries.
did not lead to an increase in the rate of side effects compared with
, and side effects were generally mild and manageable.
Results from CheckMate 816 support the benefit of using
before surgery for people with resectable NSCLC.
: NCT02998528 (ClinicalTrials.gov).
DNA vaccination consists of administering an antigen-coding nucleotide sequence. In order to improve the efficacy of DNA vaccines, electroporation is one of the most commonly used methods to enhance ...DNA uptake. Here, we discuss additional immunological effects of electroporation that are key aspects for inducing immunity in response to DNA vaccines.
DNA vaccination consists in administering an antigen-encoding plasmid in order to trigger a specific immune response. This specific vaccine strategy is of particular interest to fight against various ...infectious diseases and cancer. Gene electrotransfer is the most efficient and safest non-viral gene transfer procedure and specific electrical parameters have been developed for several target tissues. Here, a gene electrotransfer protocol into the skin has been optimized in mice for efficient intradermal immunization against the well-known telomerase tumor antigen. First, the luciferase reporter gene was used to evaluate gene electrotransfer efficiency into the skin as a function of the electrical parameters and electrodes, either non-invasive or invasive. In a second time, these parameters were tested for their potency to generate specific cellular CD8 immune responses against telomerase epitopes. These CD8 T-cells were fully functional as they secreted IFNγ and were endowed with specific cytotoxic activity towards target cells. This simple and optimized procedure for efficient gene electrotransfer into the skin using the telomerase antigen is to be used in cancer patients for the phase 1 clinical evaluation of a therapeutic cancer DNA vaccine called INVAC-1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Introduction: Repotrectinib, a next-generation ROS1 tyrosine kinase inhibitor (TKI), has demonstrated durable activity and manageable safety in patients (pts) with locally ...advanced/metastatic ROS1+ NSCLC in the pivotal phase 1/2 TRIDENT-1 trial (NCT03093116). We report efficacy with a minimum follow-up of 14 months (mo) from start of treatment in two ROS1+ NSCLC primary efficacy cohorts and safety in all pts treated at the recommended phase 2 dose (RP2D).
Methods: Pts with ROS1+ NSCLC were assigned to 4 cohorts by treatment history: TKI-naïve, 1 TKI and no chemo, 1 TKI and 1 platinum-based chemo, and 2 TKIs and no chemo. Repotrectinib RP2D was 160 mg once daily for 14 days, then 160 mg twice daily. Phase 2 primary endpoint was confirmed objective response rate (cORR) by Blinded Independent Central Review per RECIST v1.1. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), intracranial ORR, cORR in TKI-pretreated pts with ROS1 G2032R NSCLC, and safety. Efficacy analyses included pts with ≥14 mo follow-up. Safety assessments included pts treated at RP2D across all study cohorts.
Results: At data cutoff (December 19, 2022), median (range) follow-up in the primary efficacy cohorts was 24.0 (14.2–66.6) mo in the TKI-naïve cohort (n=71) and 21.5 (14.2–58.6) mo in the 1 prior TKI and no chemo cohort (n=56). In the TKI-naïve cohort, cORR was 79% (95% CI, 68–88). Median (95% CI) DOR was 34.1 (25.6–not estimable NE) mo; estimated 12- and 18-mo DOR rates were 83% (73–93) and 79% (68–90), respectively. Median PFS (95% CI) was 35.7 (27.4–NE) mo; estimated 12- and 18-mo PFS rates were 77% (66–87) and 70% (59–81), respectively. In the 1 prior TKI and no chemo cohort, cORR was 38% (95% CI, 25–52). Median DOR (95% CI) was 14.8 (7.6–NE) mo; estimated 12-mo DOR rate was 56% (34–77). Median PFS (95% CI) was 9.0 (6.8–19.6) mo; estimated 12-mo PFS rate was 41% (27–56). The median (range) time to response was 1.8 (0.9–5.6) mo in the TKI-naïve cohort and 1.8 (1.6–3.6) mo in the 1 prior TKI and no chemo cohort. Among pts with measurable brain metastasis at baseline, intracranial ORR was 89% (95% CI, 52–100) in the TKI-naïve cohort (n=9), and 38% (95% CI, 14–68) in the 1 prior TKI and no chemo cohort (n=13). In pts with TKI-pretreated ROS1 G2032R NSCLC (n=17), cORR was 59% (33–82). Among pts receiving repotrectinib at RP2D (n=426), treatment-emergent adverse events (TEAEs) occurred in 422 (99%), most commonly dizziness (62%). Grade ≥3 TEAEs occurred in 216 (51%) and were considered treatment-related in 122 (29%). TEAEs led to dose reduction and treatment discontinuation in 38% and 7% of pts, respectively. Additional analysis in CNS efficacy and by subsequent therapies will be presented.
Conclusion: With a minimum follow-up of 14 mo in TRIDENT-1, repotrectinib continued to demonstrate durable efficacy in pts with ROS1+ NSCLC, including intracranial activity, in both TKI-naïve and 1 prior TKI and no chemo cohorts. Safety in pts treated at RP2D was manageable, consistent with previous reports in all treated pts. Prior:WCLC(Sep 10).
Citation Format: Jessica J Lin, Byoung Chul Cho, D. Ross Camidge, Sang-We Kim, Benjamin Solomon, Rafal Dziadziuszko, Benjamin Besse, Koichi Goto, Adrianus Johannes de Langen, Jürgen Wolf, Ki Hyeong Lee, Sanjay Popat, Christoph Springfeld, Misako Nagasaka, Enriqueta Felip, Nong Yang, Shun Lu, Steven Kao, Vamsidhar Velcheti, Parneet Cheema, Shanna Stopatschinskaja, Minal Mehta, Denise Trone, Felipe Ades, Christophe Y. Calvet, Alexander Drilon. Repotrectinib in patients with ROS1 fusion-positive (ROS1+) non-small cell lung cancer (NSCLC): Update from the pivotal phase 1/2 TRIDENT-1 trial abstract. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR003.
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