Clinical efficacy of atezolizumab plus bevacizumab and chemotherapy in KRAS-mutated non-small cell lung cancer with STK11, KEAP1, or TP53 comutations: subgroup results from the phase III IMpower150 trial.

BACKGROUND: The efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (mKRAS) and co-occurring STK11, KEAP1, or TP53 mutations. METHODS: Mutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774). RESULTS: Within the mKRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)-greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in mKRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS-WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11, KEAP1, and TP53; these subgroups conferred different prognostic outcomes. Within the mKRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-WT and/or KEAP1-WT. In mKRAS patients with co-occurring mSTK11 and/or mKEAP1 (44.9%) or mTP53 (49.3%), survival was longer with ABCP than with ACP or BCP. CONCLUSIONS: These analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the mKRAS and KEAP1-WT and STK11-WT population vs mKRAS and mKEAP1 and mSTK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with mKRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain.

INTRODUCTION: Final overall survival (OS) analyses are presented for EGFR mutations and liver or brain metastases subgroups in the phase 3 IMpower150 study (NCT02366143) evaluating atezolizumab plus bevacizumab plus carboplatin and paclitaxel (ABCP) or atezolizumab plus carboplatin and paclitaxel (ACP) versus bevacizumab plus carboplatin and paclitaxel (BCP). METHODS: Overall, 1202 patients (intention-to-treat population) with chemotherapy-naive, metastatic, nonsquamous NSCLC were randomized to ABCP, ACP, or BCP. Patients with treated, stable brain metastases were permitted. OS was evaluated in EGFR mutations and baseline liver metastases subgroups; rate and time to development of new brain metastases were evaluated in the intention-to-treat patients. RESULTS: At data cutoff (September 13, 2019; median follow-up, 39.3 mo), OS improvements were sustained with ABCP versus BCP in sensitizing EGFR mutations (all: hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.31-1.14; previous tyrosine kinase inhibitor [TKI]: HR = 0.74; 95% CI: 0.38-1.46) and baseline liver metastases (HR = 0.68; 95% CI: 0.45-1.02) subgroups. ACP did not have survival benefit versus BCP in sensitizing EGFR mutations (all: HR = 1.0; 95% CI: 0.57-1.74; previous TKI: HR = 1.22; 95% CI: 0.68-2.22) or liver metastases (HR = 1.01; 95% CI: 0.68-1.51) subgroups. Overall, 100 patients (8.3%) developed new brain metastases. Although not formally evaluated, an improvement toward delayed time to development was found with ABCP versus BCP (HR = 0.68; 95% CI: 0.39-1.19). CONCLUSIONS: This final exploratory analysis revealed OS benefits for ABCP versus BCP in patients with sensitizing EGFR mutations, including those with previous TKI failures, and with liver metastases, although these results should be interpreted with caution. The impact of ABCP on delaying the development of new brain lesions requires further investigation.

IMpower150 Final Overall Survival Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in First-Line Metastatic Nonsquamous NSCLC.

INTRODUCTION: We report the final overall survival (OS) analyses of atezolizumab-carboplatin-paclitaxel (ACP [experimental arm]) and OS data with approximately 39.8 months of median follow-up with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) versus bevacizumab-carboplatin-paclitaxel (BCP) in chemotherapy-naive patients with metastatic nonsquamous NSCLC in the phase 3 IMpower150 study (NCT02366143). METHODS: In this randomized, open-label study (N = 1202), coprimary end points included investigator-assessed progression-free survival and OS in intention-to-treat (ITT) wild-type (WT; no EGFR or ALK alterations) patients. Secondary and exploratory end points included OS in ITT and programmed death-ligand 1 (PD-L1) subgroups defined by the VENTANA SP142 and SP263 immunohistochemistry assays. RESULTS: At the final analysis with ACP versus BCP (data cutoff: September 13, 2019; minimum follow-up: 32.4 mo), ACP had numerical, but not statistically significant, improvements in OS (ITT-WT: median OS = 19.0 versus 14.7 mo; hazard ratio = 0.84; 95% confidence interval: 0.71-1.00). OS benefit was sustained with ABCP versus BCP (ITT-WT: 19.5 versus 14.7 mo; hazard ratio = 0.80; 95% confidence interval: 0.67-0.95). Exploratory analyses in the SP142-defined PD-L1 subgroups revealed longer median OS with ABCP and ACP versus BCP in PD-L1-high and PD-L1-positive subgroups; in the PD-L1-negative subgroups, median OS was similar with ACP and ABCP versus BCP. Safety was consistent with that in earlier analyses (data cutoff: January 22, 2018). CONCLUSIONS: At the final IMpower150 OS analysis, ACP had numerical, but not statistically significant, OS improvement versus BCP. Updated data with an additional 20 months of follow-up revealed continued OS improvement with ABCP versus BCP in all patients.

Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer.

PURPOSE: Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) demonstrated survival benefit versus bevacizumab, carboplatin, and paclitaxel (BCP) in chemotherapy-naïve nonsquamous non-small-cell lung cancer (NSCLC). We present safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in nonsquamous NSCLC. METHODS: Patients were randomly assigned to receive atezolizumab, carboplatin, and paclitaxel (ACP), ABCP, or BCP. Coprimary end points were overall survival and investigator-assessed progression-free survival. The incidence, nature, and severity of adverse events (AEs) were assessed. PROs, a secondary end point, were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-Core 30 and EORTC QLQ-Lung Cancer 13. RESULTS: Overall, 400 (ACP), 393 (ABCP), and 394 (BCP) patients were safety evaluable (ie, intention-to-treat population that received one or more doses of any study treatment). More patients had grade 3/4 treatment-related AEs during the induction versus maintenance phase (ACP, 40.5% v 8.2%; ABCP, 48.6% v 21.2%; BCP, 44.7% v 11.1%). During induction, the incidence of serious AEs (SAEs) was 28.3%, 28.5%, and 26.4% in the ACP, ABCP, and BCP arms, respectively. During maintenance, SAE incidences were 20.0%, 26.3%, and 13.0%, respectively. Completion rates of the PRO questionnaires were > 88% at baseline and remained ≥ 70% throughout most study visits. Across arms, patients on average reported no clinically meaningful worsening of global health status or physical functioning scores through cycle 13. Patients across arms rated common symptoms with chemotherapy and immunotherapy similarly. CONCLUSION: ABCP seems tolerable and manageable versus ACP and BCP in first-line nonsquamous NSCLC. Treatment tolerability differed between induction and maintenance phases across treatment arms. PROs reflect a minimal treatment burden (eg, health-related quality of life, symptoms) with each regimen.

Atezolizumab in combination with bevacizumab, paclitaxel and carboplatin for the first-line treatment of patients with metastatic non-squamous non-small cell lung cancer, including patients with EGFR mutations.

Introduction: Cancer immunotherapy has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC). However, specific patient groups (e.g. patients with activating epidermal growth factor receptor [EGFR] mutations) do not appear to derive benefit from immune checkpoint inhibitor (ICI) monotherapy. Combining ICIs, such as atezolizumab, with chemotherapy and/or targeted therapies may help to address this unmet need.Areas covered: Atezolizumab is an anti-programmed death-ligand 1 therapy for several tumor types. We review its clinical efficacy and safety in the treatment of advanced or metastatic NSCLC, with a specific focus on the combination of atezolizumab with bevacizumab, carboplatin, and paclitaxel (ABCP). Data from IMpower150 show that the ABCP regimen provided clinical benefit to patients with non-squamous NSCLC, including those with EGFR mutations.Expert opinion: Combining ICIs with chemotherapy has proven to be superior to chemotherapy alone. However, tumor resistance to ICIs will likely increase as these drugs enter earlier lines of therapy, underscoring a need for effective treatments when immunotherapy fails. Data suggest that the ABCP regimen may circumvent ICI resistance mechanisms. Continued investigation into the regimen's mechanisms, improved patient profiling/selection, and treatment personalization will drive further development/discoveries.

Atezolizumab plus bevacizumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a randomised, open-label phase 3 trial.

BACKGROUND: The IMpower150 trial showed significant improvements in progression-free and overall survival with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) versus the standard-of-care bevacizumab plus carboplatin plus paclitaxel (BCP) in chemotherapy-naive patients with non-squamous non-small-cell lung cancer. Here, we report the efficacy of ABCP or atezolizumab plus carboplatin plus paclitaxel (ACP) versus BCP in key patient subgroups. METHODS: IMpower150 was a randomised, open-label, phase 3 study done at 240 academic medical centres and community oncology practices across 26 countries worldwide. Patients with chemotherapy-naive metastatic non-small-cell lung cancer were randomly assigned (1:1:1) to receive ABCP, ACP, or BCP every three weeks. The co-primary endpoints were overall survival and investigator-assessed progression-free survival in intention-to-treat wild-type patients (patients with epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK] genetic alterations were excluded). Efficacy was assessed in key subgroups within the intention-to-treat population, including patients with EGFR mutations (both sensitising and non-sensitising; EGFR-positive) previously treated with one or more tyrosine kinase inhibitors and patients with baseline liver metastases. Overall survival in the intention-to-treat population was included among secondary efficacy endpoints. Exploratory endpoints included the proportion of patients achieving an objective response in the intention-to-treat population, including EGFR-positive patients and patients with baseline liver metastases. Data are reported as per the Jan 22, 2018, data cutoff date, at which the number of coprimary prespecified overall survival events was met in the ABCP versus BCP groups. This trial is registered with ClinicalTrials.gov, number NCT02366143, and is ongoing. FINDINGS: Between March 31, 2015, and Dec 30, 2016, 1202 patients were enrolled. 400 patients were randomly assigned to ABCP, 402 to ACP, and 400 to BCP. In EGFR-positive patients (124 of 1202), median overall survival was not estimable (NE; 95% CI 17·0-NE) with ABCP (34 of 400) and 18·7 months (95% CI 13·4-NE) with BCP (45 of 400; hazard ratio [HR] 0·61 [95% CI 0·29-1·28]). Improved overall survival with ABCP versus BCP was observed in patients with sensitising EGFR mutations (median overall survival NE [95% CI NE-NE] with ABCP [26 of 400] vs 17·5 months [95% CI 11·7-NE] with BCP [32 of 400]; HR 0·31 [95% CI 0·11-0·83]) and in the intention-to-treat population (19·8 months [17·4-24·2] vs 14·9 months [13·4-17·1]; HR 0·76 [0·63-0·93]). Improved median overall survival with ABCP versus BCP was seen in patients with baseline liver metastases (13·3 months [11·6-NE] with ABCP [52 of 400] vs 9·4 months [7·9-11·7] with BCP [57 of 400]; HR 0·52 [0·33-0·82]). Median overall survival was 21·4 months (95% CI 13·8-NE) with ACP versus 18·7 months (95% CI 13·4-NE) with BCP in EGFR-positive patients (HR 0·93 [95% CI 0·51-1·68]). No overall survival benefit was seen with ACP versus BCP in patients with sensitising EGFR mutations (HR 0·90 [95% CI 0·47-1·74]), in the intention-to-treat population (HR 0·85 [0·71-1·03]), or in patients with baseline liver metastases (HR 0·87 [0·57-1·32]). In the intention-to-treat safety-evaluable population, grade 3-4 treatment-related events occurred in 223 (57%) patients in the ABCP group, in 172 (43%) in the ACP group, and in 191 (49%) in the BCP group; 11 (3%) grade 5 adverse events occurred in the ABCP group, as did four (1%) in the ACP group, and nine (2%) in the BCP group. INTERPRETATION: Improved survival was noted for patients treated with ABCP compared with those given BCP in the intention-to-treat population, and in patients with baseline liver metastases. The overall survival signal in the subgroup of patients with EGFR sensitising mutations warrants further study. FUNDING: F. Hoffmann-La Roche, Genentech.

Differential regulation of PD-L1 expression by immune and tumor cells in NSCLC and the response to treatment with atezolizumab (anti-PD-L1).

Programmed death-ligand 1 (PD-L1) expression on tumor cells (TCs) by immunohistochemistry is rapidly gaining importance as a diagnostic for the selection or stratification of patients with non-small cell lung cancer (NSCLC) most likely to respond to single-agent checkpoint inhibitors. However, at least two distinct patterns of PD-L1 expression have been observed with potential biological and clinical relevance in NSCLC: expression on TC or on tumor-infiltrating immune cells (ICs). We investigated the molecular and cellular characteristics associated with PD-L1 expression in these distinct cell compartments in 4,549 cases of NSCLC. PD-L1 expression on IC was more prevalent and likely reflected IFN-γ-induced adaptive regulation accompanied by increased tumor-infiltrating lymphocytes and effector T cells. High PD-L1 expression on TC, however, reflected an epigenetic dysregulation of the PD-L1 gene and was associated with a distinct histology described by poor immune infiltration, sclerotic/desmoplastic stroma, and mesenchymal molecular features. Importantly, durable clinical responses to atezolizumab (anti-PD-L1) were observed in patients with tumors expressing high PD-L1 levels on either TC alone [40% objective response rate (ORR)] or IC alone (22% ORR). Thus, PD-L1 expression on TC or IC can independently attenuate anticancer immunity and emphasizes the functional importance of IC in regulating the antitumor T cell response.

A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non-small cell lung cancer.

AIM: The phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non-small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC. PATIENTS AND METHODS: A 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1-14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination. RESULTS: All 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a '14 days on, 7 days off' schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients. CONCLUSION: Combining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.

A Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Pictilisib in Combination with Erlotinib in Patients with Advanced Solid Tumors.

BACKGROUND: Epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K) are involved in the proliferation and survival of many cancer types. Enhanced antitumor activity may be achieved through combined inhibition of these pathways. We report results for pictilisib (GDC-0941, a class I pan-PI3K inhibitor) plus erlotinib (an EGFR tyrosine kinase inhibitor) in patients with advanced solid tumors. MATERIALS AND METHODS: A 3 + 3 dose-escalation study was carried out at a starting daily dose of 60 mg pictilisib on days 1-21 of a 28-day cycle and 150 mg erlotinib from day 2 of cycle 1. The primary objectives of the study were to assess safety and tolerability, identify dose-limiting toxicities (DLTs), estimate the maximum tolerated dose, and identify the recommended phase II dose (RP2D). Evaluation of a dose-expansion cohort at the RP2D was performed. RESULTS: Fifty-seven patients were treated in the study. All patients experienced at least one adverse event (AE). Grade ≥3 AEs, serious AEs, and deaths were reported in 38 (66.7%), 19 (33.3%), and 4 (7.0%) patients, respectively. DLTs occurred in nine patients across eight cohorts and the RP2D was determined to be 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib. Two patients (3.5%) experienced partial response and 19 (33.3%) had stable disease. CONCLUSION: Combining pictilisib with erlotinib in patients with advanced solid tumors is feasible; however, antitumor activity is limited. Additional studies may identify patients likely to benefit from combined inhibition of EGFR and PI3K pathways. IMPLICATIONS FOR PRACTICE: Combining drugs targeting different signaling pathways in cancer growth and survival could overcome drug resistance and improve antitumor activity. In this first-in-human study for the combination, addition of the PI3K inhibitor pictilisib to the EGFR tyrosine kinase inhibitor erlotinib resulted in toxicity that led to dose and schedule modifications to identify a tolerable recommended phase II dose of 340 mg pictilisib on a "5 days on, 2 days off" schedule plus 100 mg erlotinib daily. The limited antitumor activity observed, however, suggests that additional studies are needed to identify patients most likely to benefit from combined EGFR and PI3K inhibition.

Phase II Trial of Atezolizumab As First-Line or Subsequent Therapy for Patients With Programmed Death-Ligand 1-Selected Advanced Non-Small-Cell Lung Cancer (BIRCH).

Purpose BIRCH was designed to examine the efficacy of atezolizumab, a humanized anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, in advanced non-small-cell lung cancer (NSCLC) across lines of therapy. Patients were selected on the basis of PD-L1 expression on tumor cells (TC) or tumor-infiltrating immune cells (IC). Patients and Methods Eligible patients had advanced-stage NSCLC, no CNS metastases, and zero to two or more lines of prior chemotherapy. Patients whose tumors expressed PD-L1 using the SP142 immunohistochemistry assay on ≥ 5% of TC or IC (TC2/3 or IC2/3 [TC or IC ≥ 5% PD-L1-expressing cells, respectively]) were enrolled. Atezolizumab 1,200 mg was administered intravenously every 3 weeks. Efficacy-evaluable patients (N = 659) comprised three cohorts: first line (cohort 1; n = 139); second line (cohort 2; n = 268); and third line or higher (cohort 3; n = 252). The primary end point was independent review facility-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1). Secondary end points included median duration of response, progression-free survival, and overall survival (OS). Results BIRCH met its primary objective of demonstrating a significant ORR versus historical controls. With a minimum of 12 months of follow-up, the independent review facility-assessed ORR was 18% to 22% for the three cohorts, and 26% to 31% for the TC3 or IC3 subgroup; most responses are ongoing. Responses occurred regardless of EGFR or KRAS mutation status. The median OS from an updated survival analysis (minimum of 20 month follow up) for cohort 1 was 23.5 months (26.9 months for TC3 or IC3 patients); the median OS in cohorts 2 and 3 was 15.5 and 13.2 months, respectively. The safety profile was similar across cohorts and consistent with previous atezolizumab monotherapy trials. Conclusion BIRCH demonstrated responses with atezolizumab monotherapy in patients with PD-L1-selected advanced NSCLC, with good tolerability. PD-L1 status may serve as a predictive biomarker for identifying patients most likely to benefit from atezolizumab.

Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists.

A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.

Biochemical regulation of breast cancer cell expression of S1P2 (Edg-5) and S1P3 (Edg-3) G protein-coupled receptors for sphingosine 1-phosphate.

G protein-coupled receptors (GPCRs) for lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) transduce signals to many functions of normal cells. Most human cancer cells upregulate S1P and LPA GPCRs, in patterns distinctive for each type of tumor. The findings that 1-alpha, 25-dihydroxy-vitamin D(3) (VD3) and all-trans retinoic acid (RA) differentially alter expression of the predominant S1P(3) (Edg-3) R and S1P(2) (Edg-5) R in human breast cancer cells (BCCs) permitted analyses of their individual activities, despite a lack of selective pharmacological probes. S1P-evoked increases in [Ca(2+)](i) in S1P(3) R-predominant BCCs were suppressed by concentrations of VD3 and RA which decreased expression of S1P(3) Rs, despite RA-induced increases in S1P(2) Rs. S1P-elicited chemokinetic migration of S1P(3) R-predominant BCCs across a type IV collagen-coated micropore filter also was inhibited by concentrations of VD3 and RA which decreased expression of S1P(3) Rs. The RA-induced increase in expression of S1P(2) Rs did not prevent suppression by RA of S1P-elicited chemokinesis, which appears to be mediated by S1P(3) Rs, but instead exposed S1P(2) R-mediated inhibition of epidermal growth factor-stimulated chemotaxis of BCCs. In contrast, expression of the predominant LPA(2) Rs, LPA-evoked increase in [Ca(2+)](i) and LPA-stimulated chemokinetic migration were suppressed concomitantly by RA but not VD3. Thus two structurally-homologous S1P Rs of BCCs differ in coupling to [Ca(2+)](i) signaling and have opposite effects on protein growth factor-stimulated chemotaxis.

Cutting edge: suppression of T cell chemotaxis by sphingosine 1-phosphate.

Murine CD4 and CD8 T cells express predominantly types 1 and 4 sphingosine 1-phosphate (S1P) G protein-coupled receptors (designated S1P1 and S1P4 or previously endothelial differentiation gene-encoded 1 and 6) for S1P, which has a normal plasma concentration of 0.1-1 microM. S1P now is shown to enhance chemotaxis of CD4 T cells to CCL-21 and CCL-5 by up to 2.5-fold at 10 nM to 0.1 microM, whereas 0.3-3 microM S1P inhibits this chemotaxis by up to 70%. Chemotaxis of S1P(1), but not S1P(4), transfectants to CXCL1 and CXCL4 was similarly affected by S1P. Activation of CD4 T cells, which decreases S1P receptor expression, suppressed effects of S1P on chemotaxis. Pretreatment of labeled CD4 T cells with S1P before reintroduction into mice inhibited by a maximum of 75% their migration into chemokine-challenged s.c. air pouches. The S1P-S1P(1) receptor axis thus controls recruitment of naive T cells by maintaining their response threshold to diverse lymphotactic factors.

Lysophospholipid mediators of immunity and neoplasia.

Lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P) and some other structurally related lysophospholipids are active growth factors and stimuli for diverse cellular functions. LPA and S1P promote early T cell migration to tissue sites of immune responses and regulate T cell proliferation and secretion of numerous cytokines. Edg-4 (LPA2) LPA receptors, which are constitutively expressed by helper T cells, and Edg-2 (LPA1) LPA receptors, which are expressed only by activated helper T cells, transduce opposite effects of LPA on some T cell responses. A similar mechanism is observed for fine regulation of Edg R-mediated effects of LPA on ovarian cancer cells. Edg-4 (LPA2) R transduces proliferative responses, recruitment of autocrine protein growth factors, and migration of ovarian cancer cells, whereas Edg-2 (LPA1) R transduces inhibition of Edg-4 (LPA2) R-mediated responses and concurrently elicits apoptosis and anoikis of ovarian cancer cells. Edg-4 (LPA2) R is a distinctive functional marker for ovarian carcinoma, and is expressed both as the wild-type and a carboxyl-terminally extended gain-of-function mutant. Newly discovered non-lipid agonists and antagonists for individual Edg receptors will permit more sophisticated analyses of their respective contributions in human biology and pathophysiology, and may represent novel therapeutic modalities in immune disorders and cancer.

Lysophospholipid growth factors and their G protein-coupled receptors in immunity, coronary artery disease, and cancer.

The physiological lysophospholipids (LPLs), exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are omnific mediators of normal cellular proliferation, survival, and functions. Although both LPA and S1P attain micromolar concentrations in many biological fluids, numerous aspects of their biosynthesis, transport, and metabolic degradation are unknown. Eight members of a new subfamily of G protein-coupled LPA/S1P receptors, originally termed Edg Rs, bind either LPA or S1P with high affinity and transduce a series of growth-related and/or cytoskeleton-based functional responses. The most critical areas of LPL biology and pathobiology are neural development and neurodegeneration, immunity, atherosclerosis and myocardial injury, and cancer. Data from analyses of T cells established two basic points: (1) the plasticity and adaptability of expression of LPA/S1P Rs by some cells as a function of activation, and (2) the role of opposing signals from two different receptors for the same ligand as a mechanism for fine control of effects of LPLs. In the heart, LPLs may promote coronary atherosclerosis, but are effectively cytoprotective for hypoxic cardiac myocytes and those exposed to oxygen free radicals. The findings of production of LPA by some types of tumor cells, overexpression of selected sets of LPA receptors by the same tumor cells, and augmentation of the effects of protein growth factors by LPA have suggested pathogenetic roles for the LPLs in cancer. The breadth of physiologic and pathologic activities of LPLs emphasizes the importance of developing bioavailable nonlipid agonists and antagonists of the LPA/S1P receptors for diverse therapeutic applications.