Efficacy Of Chemoimmunotherapy Research Articles

Durvalumab with etoposide and carboplatin for patients with extensive-stage small cell lung cancer and interstitial lung disease: A multicenter, open-label prospective trial

ObjectivesCertain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP). MethodsIn this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate. ResultsTwenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3–99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6–6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached). ConclusionsChemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP.

Effect of TTF-1 expression on progression free survival of immunotherapy and chemo-/immunotherapy in patients with non-small cell lung cancer

BackgroundThe choice between immunotherapy with a checkpoint inhibitor (CPI) and chemo-/immunotherapy (CIT) in patients with NSCLC stage IV is often discussed. There is some data that the effect of chemotherapy is influenced by TTF-1 expression. Little is known about the influence of thyreoid transcription factor 1 (TTF-1) expression on CIT and CPI therapy. We aimed to investigate the relationship between tumor TTF-1 expression and efficacy of CIT and CPI therapy.Patients and methodsWe retrospectively analysed 130 patients (age 68 ± 7 y) with NSCLC stage IV. Only patients with lung adenocarcinoma were included. Patients with ALK, ROS1, RET, MET, NTRK, EGFR, BRAF mutation were excluded. Patients were treated according to the guidelines with either CPI alone (pembrolizumab, nivolumab, atezolizumab, cemiplimab) or CIT (Carboplatin/Pemetrexed/Pembrolizumab, Carboplatin/Paclitaxel/Atezolizumab). We registered patients’ characteristics including TTF-1 expression. Group 1 consisted of 40 patients with CPI and TTF-1 expression, group 2 were 26 patients with CPI and with no TTF-1 expression. Group 3 consisted of 41 patients with CIT and TTF-1 expression, group 4 were 23 patients with CIT and with no TTF-1 expression.ResultsGroup 1–4 showed comparable patients characteristics. Using cox-regression analysis, we found that TTF-1 expression resulted in an improved progression free survival (PFS) compared to patients with CPI and no TTF-1 expression (18 ± 3,15 vs. 5 ± 0,85 months, p = 0.004, 95% CI: 0,23 − 0,984). In patients, who were treated with CIT, PFS was also increased in patients with TTF-1 expression (9 ± 3,17 vs. 3 ± 0,399 months, p = 0.001, 95% CI: 0,23 − 0,85).ConclusionsIn a real-life setting, we found that TTF-1 expression is associated with an increased PFS. Patients with chemo-/immunotherapy and immunotherapy seem to have a better therapy response in pulmonary adenocarcinoma with TTF-1 expression.

Gold Nano Frameworks with Mesopores for Synergistic Immune-Thermal Therapy in Hepatic Carcinoma: A Paradigm Shift in Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB) therapy, while showing promise in various cancers, exhibits limited effectiveness in hepatic carcinoma due to the tumor's immunosuppressive microenvironment (TME) and challenges associated with immune cell infiltration. Efforts to transform the "cold" TME into an "inflamed" state, notably through chemo-immunotherapy, have sparked interest due to their potential to induce immunogenic cell death and augment the infiltration of cytotoxic T lymphocytes (CTLs). Nonetheless, the efficacy of chemo-immunotherapy is often compromised by suboptimal pharmacokinetics, poor tumor accumulation, and off-target toxicity. Herein, in response, we introduce an innovative, milder thermal therapeutic approach leveraging gold nano frameworks with mesopores for the targeted delivery of the immunostimulant imiquimod and NIR-II photothermal therapy. This strategy employs targeted molecule modifications to ensure precise tumor targeting, guided by photoacoustic imaging. Subsequent to mild thermal treatment, there is a release of immunogenic proteins (CRT and HSP90), enhancing tumor immunogenicity. Assisted by imiquimod, substantial CTL infiltration occurs, accompanied by pro-inflammatory factor release (TNF-α, IL-6), transforming M2 macrophages into the M1 phenotype. Ultimately, the proposed strategy combines PD-L1/PD-1 blockade, imiquimod and mild thermal treatment to synergistically enhance tumor immunogenicity, remodel the TME, and restrain hepatic carcinoma, making strides in ICB synergistic immune-thermal therapy.

TFEB controls sensitivity to chemotherapy and immuno-killing in non-small cell lung cancer

BackgroundIn non-small cell lung cancer (NSCLC) the efficacy of chemo-immunotherapy is affected by the high expression of drug efflux transporters as ABCC1 and by the low expression of ABCA1, mediating the isopentenyl pyrophosphate (IPP)-dependent anti-tumor activation of Vγ9Vδ2 T-lymphocytes. In endothelial cells ABCA1 is a predicted target of the transcription factor EB (TFEB), but no data exists on the correlation between TFEB and ABC transporters involved in the chemo-immuno-resistance in NSCLC.MethodsThe impact of TFEB/ABCC1/ABCA1 expression on NSCLC patients’ survival was analyzed in the TCGA-LUAD cohort and in a retrospective cohort of our institution. Human NSCLC cells silenced for TFEB (shTFEB) were analyzed for ABC transporter expression, chemosensitivity and immuno-killing. The chemo-immuno-sensitizing effects of nanoparticles encapsulating zoledronic acid (NZ) on shTFEB tumors and on tumor immune-microenvironment were evaluated in Hu-CD34+ mice by single-cell RNA-sequencing.ResultsTFEBlowABCA1lowABCC1high and TFEBhighABCA1highABCC1low NSCLC patients had the worst and the best prognosis, respectively, in the TCGA-LUAD cohort and in a retrospective cohort of patients receiving platinum-based chemotherapy or immunotherapy as first-line treatment. By silencing shTFEB in NSCLC cells, we demonstrated that TFEB was a transcriptional inducer of ABCA1 and a repressor of ABCC1. shTFEB cells had also a decreased activity of ERK1/2/SREBP2 axis, implying reduced synthesis and efflux via ABCA1 of cholesterol and its intermediate IPP. Moreover, TFEB silencing reduced cholesterol incorporation in mitochondria: this event increased the efficiency of OXPHOS and the fueling of ABCC1 by mitochondrial ATP. Accordingly, shTFEB cells were less immuno-killed by the Vγ9Vδ2 T-lymphocytes activated by IPP and more resistant to cisplatin. NZ, which increased IPP efflux but not OXPHOS and ATP production, sensitized shTFEB immuno-xenografts, by reducing intratumor proliferation and increasing apoptosis in response to cisplatin, and by increasing the variety of anti-tumor infiltrating cells (Vγ9Vδ2 T-lymphocytes, CD8+T-lymphocytes, NK cells).ConclusionsThis work suggests that TFEB is a gatekeeper of the sensitivity to chemotherapy and immuno-killing in NSCLC, and that the TFEBlowABCA1lowABCC1high phenotype can be predictive of poor response to chemotherapy and immunotherapy. By reshaping both cancer metabolism and tumor immune-microenvironment, zoledronic acid can re-sensitize TFEBlow NSCLCs, highly resistant to chemo- and immunotherapy.

Clinical significance and biological function of interferon regulatory factor 1 in non-small cell lung cancer.

The clinical application and biological function of interferon regulatory factor 1 (IRF1) in non-small cell lung cancer (NSCLC) patients undergoing chemoimmunotherapy remain elusive. The aim of this study was to investigate the predictive and prognostic significance of IRF1 in NSCLC patients. We employed the cBioPortal database to predict frequency changes in IRF1 and explore its target genes. Bioinformatic methods were utilized to analyze the relationship between IRF1 and immune regulatory factors. Retrospective analysis of clinical samples was conducted to assess the predictive and prognostic value of IRF1 in chemoimmunotherapy. Additionally, A549 cells with varying IRF1 expression levels were constructed to investigate its effects on NSCLC cells, while animal experiments were performed to study the role of IRF1 in vivo. Our findings revealed that the primary mutation of IRF1 is deep deletion and it exhibits a close association with immune regulatory factors. KRAS and TP53 are among the target genes of IRF1, with interferon and IL-2 being the predominantly affected pathways. Clinically, IRF1 levels significantly correlate with the efficacy of chemoimmunotherapy. Patients with high IRF1 levels exhibited a median progression-free survival (mPFS) of 9.5 months, whereas those with low IRF1 levels had a shorter mPFS of 5.8 months. IRF1 levels positively correlate with PD-L1 distribution and circulating IL-2 levels. IL-2 enhances the biological function of IRF1 and recapitulates its role in vivo in the knockdown group. Therefore, IRF1 may possess predictive and prognostic value for chemoimmunotherapy in NSCLC patients through the regulation of the IL-2 inflammatory pathway.

Abstract 3864: Role of NK/TAM cross-talk on T-CD8+ recruitment and efficacy of chemoimmunotherapy and MEKi combination in "cold" tumors

Abstract In patients with non-small cell lung cancer (NSCLC), double platinum-based chemotherapy (cisplatin or carboplatin and pemetrexed) combined with the anti-PD-1 antibody has shown significant clinical benefit and has become the standard of care. In the context of so-called "cold" tumors, the immunogenic capacities of chemotherapies increase danger signals (type I IFNs, CXCL9/10) and favor both infiltration of NK/T-CD8+ cells and response to anti-PD-1. Despite the therapeutic progress represented by this new combination, some patients have limited benefit from chemo-immunotherapy, suggesting that in these patients, the immunogenic capacities of chemotherapy are limited. Recently, we were able to show that KRAS oncogene signaling restricts the ability of the cisplatin/pemetrexed doublet to induce the chemokine CXCL10, lymphocyte recruitment and sensitize to PD-L1 blockade. Thus, the addition of a MEK inhibitor (MEKi) to the chemo-immunotherapy combination restores an immunogenic signal through CXCL10, enabling T-CD8+ to infiltrate the tumor more extensively, making it more sensitive to immunotherapy. Here, we unravel the essential role of NK cells in the immunological and antitumoral effect of chemo-immunotherapy plus MEKi combination in the LLC1 preclinical lung cancer model. We showed that chemo/MEKi combination favors NK cell recruitment and activation in tumor bed through both CXCL10 and NKG2D-ligand (Rae1, Mult1). Then, IFNγ-producing NK cells trigger tumor associated macrophage switch from M2 toward M1 phenotype and amplify T-CD8+ cells recruitment through CXCL9 production by macrophages. Thus, NK cell depletion, CXCR3, CXCL9 or NKG2D-neutralization restrained chemo/MEKi therapeutic efficacy. However, IFNγ also triggers NKG2A-ligand expression (Qa-1b, HLA-E in human) which restrained NK cell activation and CD8+ T cell recruitment. Thus reducing the NKG2A pathway, by using Qa-1b-/- LLC1 cells, enhances chemo-immunotherapy/MEKi anti-tumor efficacy. Similar results were obtained in preclinical “cold” CT26 colon cancer model treated by chemo-immunotherapy. Our results underline a new role for NK cell activation to trigger TAM2/TAM1 switch, CXCL9 expression and amplify CD8 T cell recruitment in “cold” tumor. In a context of resistance to chemo-immunotherapy, MEKi or ICI targeting NK cells could be an interesting way to amplify the anti-tumor immune response by modulating both TAMs biology and the recruitment of CD8+ T cells. Citation Format: Lisa Nuttin, Charlène Latour, Solène Revy, Romain Aucagne, Guilhem Lalle, François Ghiringhelli, Emeric Limagne. Role of NK/TAM cross-talk on T-CD8+ recruitment and efficacy of chemoimmunotherapy and MEKi combination in "cold" tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3864.

First-Line Chemoimmunotherapy versus Sequential Platinum-Based Chemotherapy Followed by Immunotherapy in Patients with Non-Small Cell Lung Cancer with ≤49% Programmed Death-Ligand 1 Expression: A Real-World Multicenter Retrospective Study.

The long overall survival (OS) observed among patients with non-small cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression in chemoimmunotherapy (CIT) groups in previous phase III trials suggests the limited efficacy of CIT among the subgroup with ≤49% PD-L1 expression on tumor cells. Hence, sequential treatment with first-line platinum-based chemotherapy followed by second-line immune checkpoint inhibitor treatment (SEQ) is an option. This study examined whether first-line CIT would provide better outcomes than SEQ in patients with advanced NSCLC with ≤49% PD-L1 expression. This retrospective study evaluated patients with untreated NSCLC who received first-line CIT or SEQ at nine hospitals in Japan. OS, progression-free survival (PFS), PFS-2 (the time from first-line treatment to progression to second-line treatment or death), and other related outcomes were evaluated between the CIT and SEQ groups. Among the 305 enrolled patients, 234 eligible patients were analyzed: 165 in the CIT group and 69 in the SEQ group. The COX proportional hazards model suggested a significant interaction between PD-L1 expression and OS (p = 0.006). OS in the CIT group was significantly longer than that in the SEQ group in the 1-49% PD-L1 expression subgroup but not in the <1% PD-L1 expression subgroup. Among the subgroup with 1-49% PD-L1 expression, the CIT group exhibited longer median PFS than the SEQ group (CIT: 9.3 months (95% CI: 6.7-14.8) vs. SEQ:5.5 months (95% CI: 4.5-6.1); p < 0.001), while the median PFS in the CIT group was not statistically longer than the median PFS-2 in the SEQ group (p = 0.586). There was no significant difference between the median PFS in the CIT and SEQ groups among the <1% PD-L1 expression subgroup (p = 0.883); the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group (10.5 months (95% CI: 5.9-15.3) vs. 6.4 months (95% CI: 4.9-7.5); p = 0.024). CIT is recommended for patients with NSCLC with 1-49% PD-L1 expression because it significantly improved OS and PFS compared to SEQ. CIT had limited benefits in patients with <1% PD-L1 expression, and the median PFS-2 in the SEQ group was significantly longer than the median PFS in the CIT group. These findings will help physicians select the most suitable treatment option for patients with NSCLC, considering PD-L1 expressions.

Chemoimmunotherapy in patients with extensive-stage small cell lung cancer and a poor performance status.

Immune checkpoint inhibitor combined with platinum-etoposide is the standard first-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). The phase 3 clinical trials that led to the approval of chemoimmunotherapy in ES-SCLC excluded patients who had an Eastern Cooperative Group (ECOG) performance status (PS) of 2-3. Therefore, data on the efficacy of chemoimmunotherapy in patients with an ECOG PS of 2-3 are limited. A retrospective analysis was performed on patients diagnosed with ES-SCLC who received chemoimmunotherapy (atezolizumab or durvalumab) within the Mayo Clinic Health System between January 2016 and January 2021. The objective of this study was to compare the overall survival (OS), progression-free survival (PFS), and best clinical response to therapy in patients with an ECOG PS of 0-1 vs. patients with an ECOG PS of 2-3 who received chemoimmunotherapy for newly diagnosed ES-SCLC. In total, 82 patients were included in the study. The mean±standard deviation age was 68.1±8.3 years. Of these, 56 patients were identified with an ECOG PS of 0-1, and 26 patients were identified with an ECOG PS of 2-3. The median PFS was similar regardless of ECOG PS (5.8months [95% CI, 4.3-6.0 months] in the ECOG PS 0-1 group vs. 4.1months [95% CI, 3.8-6.9 months] in the ECOG PS 2-3; p=.2994). The median OS was also similar regardless of ECOG PS (10.6months [95% CI, 8.4-13.4 months] in the ECOG PS 0-1 group vs. 9.3months [95% CI, 4.9-12.8 months]; p=.2718) in the ECOG PS 2-3 group. The study results demonstrated no significant difference in PFS or OS among the ECOG PS 2-3 and ECOG PS 0-1 groups. Therefore, chemoimmunotherapy should be considered for patients who have ES-SCLC with an ECOG PS of 2-3.

Efficacy of chemoimmunotherapy in a lung adenocarcinoma patient with mutations in the KRAS and STK11

Efficacy of chemoimmunotherapy in a lung adenocarcinoma patient with mutations in the KRAS and STK11

Clinicopathologic and Genomic Factors Impacting Efficacy of First-Line Chemoimmunotherapy in Advanced NSCLC

IntroductionAlthough programmed cell death protein 1 and programmed death-ligand 1 (PD-L1) blockade in combination with platinum-doublet chemotherapy has become a mainstay of first-line treatment for advanced NSCLC, factors associated with efficacy of chemoimmunotherapy (CIT) are not well characterized. MethodsIn this multicenter retrospective analysis, clinicopathologic and genomic data were collected from patients with advanced NSCLC (lacking sensitizing genomic alterations in EGFR and ALK) and evaluated with clinical outcomes to first-line CIT. ResultsAmong 1285 patients treated with CIT, a worsening performance status and increasing derived neutrophil-to-lymphocyte ratio in the blood were associated with a significantly reduced objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS). With increasing PD-L1 tumor proportion scores of less than 1%, 1% to 49%, 50% to 89%, and greater than or equal to 90%, there was a progressive improvement in ORR (32.7% versus 37.5% versus 51.6% versus 61.7%, p < 0.001), mPFS (5.0 versus 6.1 versus 6.8 versus 13.0 mo, p < 0.001), and generally mOS (12.9 versus 14.6 versus 34.7 versus 23.1 mo, p = 0.009), respectively. Of 789 NSCLCs with comprehensive genomic data, NSCLCs with a tumor mutational burden (TMB) greater than or equal to the 90th percentile had an improved ORR (53.5% versus 36.4%, p = 0.004), mPFS (10.8 versus 5.5 mo, p < 0.001), and mOS (29.2 versus 13.1 mo, p < 0.001), compared with those with a TMB less than the 90th percentile. In all-comers with nonsquamous NSCLC, the presence of an STK11, KEAP1, or SMARCA4 mutation was associated with significantly worse ORR, mPFS, and mOS to CIT (all p < 0.05); this was also observed in the KRAS-mutant subgroup of NSCLCs with co-occurring mutations in STK11, KEAP1, or SMARCA4 (all p < 0.05). In KRAS wild-type NSCLC, KEAP1 and SMARCA4 mutations were associated with a significantly shorter mPFS and mOS to CIT (all p < 0.05), but STK11 mutation status had no significant impact on mPFS (p = 0.16) or mOS (p = 0.38). ConclusionsIn advanced NSCLC, better patient performance status, low derived neutrophil-to-lymphocyte ratio, increasing PD-L1 expression, a very high TMB, and STK11/KEAP1/SMARCA4 wild-type status are associated with improved clinical outcomes to first-line CIT.

Tolerability and efficacy of chemoimmunotherapy when administered with a corticosteroid-free anti-emetic regimen.

The use of immune checkpoint inhibitors (ICIs) in combination with chemotherapy is commonplace. This study sought to determine whether the omission of corticosteroids from the antiemetic regimen in patients receiving chemoimmunotherapy changes control of nausea and time on ICI therapy. This single-site, retrospective, observational study was conducted at Veteran Health Indiana, a level 1A Veterans Affairs tertiary care facility. All patients who received concurrent chemoimmunotherapy between January 1, 2018, and December 31, 2020, were included. The replacement of corticosteroids with olanzapine in chemoimmunotherapy regimens occurred on March 27, 2019. Outcomes were compared in patients who received corticosteroids as part of antiemetic prophylaxis versus patients in whom corticosteroids were omitted. Outcomes included the proportion of patients achieving an anti-nausea complete control response (CCR) or partial control response (PCR) with antiemetic prophylaxis, and the time on ICI therapy in months. Seventy-two patients received a chemotherapeutic agent with a concomitant ICI during the designated time frame and were included for anti-emetogenic and ICI efficacy analysis, 36 patients received corticosteroids with chemoimmunotherapy and 36 patients did not. CCR was achieved in 55.6% of patients who received corticosteroids and in 69.4% of patients who did not. PCR was 19.4% versus 25.0%, respectively. Removal of corticosteroids from chemoimmunotherapy regimens did not result in a significant difference in nausea control or time on ICI therapy. Results suggest corticosteroids may be safely continued, or removed and replaced by other novel agents for chemotherapy-induced nausea and vomiting when administered with ICIs.

Efficacy of Chemoimmunotherapy in NSCLC Patients With Brain Metastasis With or Without Prior Brain Radiotherapy.

Many patients with advanced lung cancer develop brain metastasis (BM); however, few reports confirming the efficacy of immune checkpoint inhibitors (ICIs) plus chemotherapy in non-small cell lung cancer (NSCLC) patients with symptomatic BM have been published. Therefore, we retrospectively evaluated the effects of chemoimmunotherapy in NSCLC patients who did or did not receive prior brain radiotherapy. A total of 103 patients with advanced NSCLC who received ICIs plus chemotherapy at our hospital from January 2019 to July 2021 were retrospectively enrolled. Patients with BM tended to have shorter progression-free survival (PFS) and overall survival (OS) compared with patients without BM. The maximum size of BM and the proportion of patients with symptomatic BM were greater among patients who received brain radiotherapy before chemoimmunotherapy. However, patients who received prior brain radiotherapy had better PFS and OS compared with patients who did not receive prior brain radiotherapy. Patients who received prior brain radiotherapy experienced a superior therapeutic benefit of ICIs plus chemotherapy, including those with larger and more symptomatic BM.

1147P Effects of the use of antibiotics or antacids on chemoimmunotherapy prognostic factors in patients with advanced non-small cell lung cancer: A propensity-score-matched analysis

The gut microbiota is an immune-specific biomarker of cancer immunotherapy. Antibiotic- or antacid-induced dysbiosis negatively impacts clinical outcomes of immunotherapy. However, the impact of dysbiosis on the efficacy of chemoimmunotherapy, the standard of care in first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC), remains unknown. Therefore, this study aimed to evaluate the impact of chemoimmunotherapy in patients with NSCLC exposed to antibiotics or antacids.

Abstract 2207: Upfront metronomic chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

Abstract Background and purpose: For squamous cell lung carcinoma (SQCLC), the survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immune checkpoint inhibitors (ICIs), also known as chemoimmunotherapy, have been confirmed in recent clinical trials. Nevertheless, the actual relationship between MTD chemotherapy and ICIs remains controversial, as most oncologists considered that MTD chemotherapeutic agents could cause immunosuppression. Hence, we attempted to optimize and assess different combinatorial patterns of chemoimmunotherapy in SQCLC. Methods: We utilized the in vitro SQCLC cell lines, in vivo syngeneic immunocompetent mouse models, and patient samples to fully explore how to increase the ectopic lymphoid-like structures (ELSs) and the therapeutic targets for anti-programmed death 1 (PD-1) / anti PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), as well as the underlying mechanisms, in order to render SQCLC to be more sensitive to ICIs and improve the efficacy of chemoimmunotherapy. Results: Low-dose chemotherapeutic agents induced SQCLC cells to undergo immunogenic cell death (ICD) by activating the PI3K/Akt/NF-κB signaling pathway and thereby enhancing neoantigen exposure. Following, the high mobility group box-1 released by cells undergoing ICD promoted neoantigen uptake and presentation by activating dendritic cells (DCs) and consequently invoking specific T cell responses. In vivo, low-dose chemotherapeutic agents activated systemic immune responses and immunological memory, and enhanced antitumor ELSs compared with routine MTD chemotherapy. Moreover, the upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and synergized better with the subsequent administration of anti-PD-1/PD-L1 mAbs. One possible mechanism of this synergy is increasing the activated type I macrophages, DCs, and cytotoxic CD8+ T cells, and maintaining the diversity and normal composition of intestinal gut microbiota. In contrast, when combined with ICIs, the effects of routine MTD chemotherapy appeared to be additive rather than synergistic. Conclusion: The upfront metronomic chemotherapy better synergizes with immunotherapy over the routine MTD chemotherapy in SQCLC. This preclinical study provides a novel strategy to optimize chemoimmunotherapy, and it is worth being translated into the clinic in the future. Citation Format: Xi-Ran He, Yang Du, Yu-Shen Jin, Hua Bai, Jie Tian, Jie Wang. Upfront metronomic chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2207.

Comparative efficacy of chemoimmunotherapy versus immunotherapy alone in the front-line treatment of advanced non-small cell lung cancer: A systematic review and network meta-analysis.

9552 Background: Immune checkpoint inhibitors (ICI) and combination chemotherapy (chemo) plus ICI (Chemo-ICI) have been shown in RCTs to have improved OS compared to chemo in the 1L treatment of advanced NSCLC. However, the benefit of chemo-ICI compared with ICI alone is unknown. Methods: Systematic review using MEDLINE, Embase and Cochrane CENTRAL was done to identify relevant studies up to December 2019. Phase 3 RCTs that evaluated the efficacy of 1L ICI or chemo-ICI and reported outcomes stratified by PD-L1 status (&lt;1%, 1-49%, ≥50%) were included. ICI was defined as single-agent PD-1 axis inhibitor or dual checkpoint blockade with PD-1 axis inhibitor plus CTLA-4 inhibitor. Comparison for PD-L1&lt;1% included chemo-ICI vs ipi/nivo and for PD-L1 1-49% and PD-L1&gt;50% included chemo-ICI vs ipi/nivo or single-agent ICI. OS, PFS, and ORR were extracted. Network meta-analysis (NMA) was done in Bayesian random-effects regression models. Results: Ten phase 3 RCTs (7971 screened) involving 7,218 patients assigned to ICI (pembro or atezo or ipi/nivo) or chemo-ICI (platinum-doublet + atezo, pembro, or nivo) were included. In PD-L1 &lt;1% patients, NMA comparing chemo-ICI with ipi/nivo failed to show a statistically significant difference in OS, PFS or ORR. In PD-L1 1-49% patients, there was no significant difference between chemo-ICI vs ICI in OS or ORR; PFS could not be analyzed due to lack of available data. In PD-L1 &gt;50% patients, chemo-ICI was associated with improved PFS and ORR compared to ICI alone, but without any OS difference (Table). Conclusions: Although the addition of chemo to ICI appears to improve ORR and PFS in PD-L1 ≥50% patients when compared to ICI alone, chemo-ICI does not confer an OS benefit in the 1L treatment of NSCLC patients regardless of PD-L1 status. Prospective trials comparing chemo-ICI, ICI monotherapy, and combination ICI are needed to confirm these findings. OS, PFS and ORR with chemo-ICI vs ICI. [Table: see text]

The impact of antibiotic usage on the efficacy of chemoimmunotherapy is contingent on the source of tumor-reactive T cells.

In recent years the combined use of chemotherapy and immunotherapy, collectively termed chemoimmunotherapy, has emerged as a promising treatment option for patients with cancer. Antibiotics are commonly used to reduce infection-related complications in patients undergoing chemotherapy. Intriguingly, accumulating evidence has implicated gut microbiota as a critical determinant of host antitumor immune responses, raising the question as to whether the use of broad-spectrum antibiotics would invariably diminish tumor response to chemoimmunotherapies. We investigated the impact of antibiotics on the therapeutic outcomes of cyclophosphamide (CTX) chemotherapy and adoptive T-cell therapy (ACT) where CTX was used as the host-conditioning regimen in mice. We show that antibiotic prophylaxis dampened the endogenous T cell responses elicited by CTX, and reduced the efficacy of CTX against B-cell lymphoma. In the ACT setting, antibiotics administration impaired the therapeutic effects of adoptively transferred tumor-specific CD4+ T cells in mice with implanted colorectal tumors. In contrast, long-term antibiotic exposure did not affect the efficacy of ACT using CD19-targeting chimeric antigen receptor (CAR) T cells in mice with systemic B-cell lymphoma, although it correlated with prolonged CAR expression and sustained B-cell aplasia. Our study demonstrates that chemoimmunotherapies may have variable reliance on intestinal microbiota for T cell activation and function, and thus have different sensitivities to antibiotic prophylaxis. These findings may have implications for the judicial use of antibiotics in cancer patients receiving chemoimmunotherapies.

Exploiting metabolic inhibition to eradicate residual tumors after chemo-immunotherapy

Cancer cells have long been known to exhibit metabolic reprogramming which involves a shift towards glycolysis. The enhanced glycolysis of cancer cells not only impose nutrient restriction in the tumor microenvironment, but also contribute to the acidic environment which is hostile to the invading anti-tumor immune cells. Hence, targeting the glycolysis dependency of tumor cells has been exploited for therapy. The glucose anti-metabolite, 2-deoxyglucose (2DG), a competitive inhibitor of glucose transport and glucose phosphorylation by hexokinase, has been extensively tested in various animal models and clinical trials. Although 2DG as anti-cancer agent showed a limited efficacy, its combined use with other treatment modalities, including chemotherapy and radiotherapy, has shown encouraging results. In particular, it has been shown that the combination of 2DG and cytotoxic agent etoposide resulted in enhanced antitumor immune responses, suggesting the therapeutic potential of combining chemotherapy, immunotherapy and glycolysis inhibition. We set out to study how metabolic inhibition alters the tumor microenvironment and how it can be utilized to augment the efficacy of chemo-immunotherapy. We found that glycolysis inhibition alone was detrimental to adoptive T-cell therapy (ACT). However, a rational combination of chemotherapy, ACT and 2DG led to tumor eradication and long-term survival in mice. The underlying mechanism of this synergy will be discussed.

Chemoimmunotherapy of syngeneic mouse mammary carcinomas employing methanol extraction residue.

Isografts of two mammary carcinomas, one spontaneously arising in a BALB/cfC3H female infected with MTV and one free of MTV (tumor D7T4S), were removed surgically from Balb/c (MTV free) female hosts, and fragments of each tumor were immediately reimplanted in situ (simulated local recurrence challenge). The animals were then subjected to treatment with the MER fraction of tubercle bacilli, with one of three chemotherapeutic drugs (5-FU, cyclophosphamide, and methotrexate), or with both MER and one of the chemotherapeutic agents (chemoimmunotherapy). The incidence of progressively developing recurrence tumors and the longevity of the animals were determined. The therapeutic effects of treatment with MER alone were ascertained by comparing groups of mice that received the fraction by various schedules with saline-injected control groups; the efficacy of chemoimmunotherapy was assassed by comparing groups that received MER plus one of the drugs with groups subjected to drug intervention by itself. MER administered alone did not reduce the incidence of recurrent tumors but was consistently efficacious in prolonging the lives of animals challenged with the MTV (+) carcinoma, although considerably less so in animals tested with the weakly immunogenic tumor D7T4S. A negative effect by MER on tumor frequency did not occur and was seen only once with regard to host life duration. Combined intervention with MER and 5-FU proved to be significantly and consistently superior to similar treatment with only 5-FU in animals challenged with the MTV(+) carcinoma. No such additive action by MER plus 5-FU was seen in mice challenged with D7T4S, however, nor did the other two chemoimmunotherapeutic regimens differ significantly in therapeutic efficacy from the corresponding chemotherapy alone in most of the trials with both tumors.