We report here that cells co-purifying with mesenchymal stem cells--termed here multipotent adult progenitor cells or MAPCs--differentiate, at the single cell level, not only into mesenchymal cells, but also cells with visceral mesoderm, neuroectoderm and endoderm characteristics in vitro. When injected into an early blastocyst, single MAPCs contribute to most, if not all, somatic cell types. On transplantation into a non-irradiated host, MAPCs engraft and differentiate to the haematopoietic lineage, in addition to the epithelium of liver, lung and gut. Engraftment in the haematopoietic system as well as the gastrointestinal tract is increased when MAPCs are transplanted in a minimally irradiated host. As MAPCs proliferate extensively without obvious senescence or loss of differentiation potential, they may be an ideal cell source for therapy of inherited or degenerative diseases.

Summary Background Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab. Methods We assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827. Findings Between May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8–34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34–0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1–8·6] vs 2·1 months [1·6–2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30–0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1–10·4] vs 2·0 months [1·8–2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36–0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5–18·9] vs 5·3 months [2·7–7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36–0·96], p=0·034; median ...

Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

Background Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. Patients and methods We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. Results Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR ( EGFR Δ19 ) but similar for EGFR L858R lung tumors. EGFR T790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFR Δ19 alterations harbored a lower tumor mutation burden compared with EGFR L858R lung tumors despite similar smoking history. Conclusions EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.

Background Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases/year in the USA, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV-oncoprotein (T-antigens) have been correlated with MCC tumor burden. We prospectively validated the clinical utility of MCPyV oncoprotein antibody titers for MCC prognostication and surveillance. Methods MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly-diagnosed MCC were followed prospectively (median follow-up 1.9 years). Among seropositive patients, antibody titer and disease status were serially tracked. Results Antibodies to MCPyV-oncoproteins were rare among healthy individuals (1%) but present in most MCC patients (114 of 219, 52%, p<0.01). Seropositivity at diagnosis independently predicted decreased recurrence risk (HR=0.58; p=0.04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. Following initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 timepoints), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence while a decreasing titer had a negative predictive value of 97%. Conclusions Determination of oncoprotein antibody titer assists in the clinical management of newly diagnosed MCC patients by stratifying them into a higher risk seronegative cohort in whom radiologic imaging may play a more prominent role, and into a lower-risk seropositive cohort whose disease status can be tracked in part via oncoprotein antibody titer.

We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti-PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy.

Purpose Several biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non-small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long term benefit. Experimental Design We assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4 and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8 to 5.5 years). Results PD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among five patients with long-term survival >3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited. Conclusion In NSCLC patients treated with PD-1 blockade with long term follow up, TMB, PD-L1 and CD8 were each associated with benefit from PD-1 blockade. Pre-treatment PD-L1 expression was correlated with T lymphocyte infiltration as well as OS, while models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.

Background: Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate consisting of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Preliminary results from the phase 1 TROPION-PanTumor01 study demonstrate that Dato-DXd has encouraging antitumor activity and a manageable safety profile in patients with non-small cell lung cancer (NSCLC) (Meric-Bernstam, ASCO 2021) and those with triple-negative breast cancer (TNBC) (Bardia, ESMO BC 2021). Updated results from the TNBC cohort are presented here. Methods: TROPION-PanTumor01 (NCT03401385) is a phase 1, multi-center, open-label, 2-part study evaluating Dato-DXd in previously treated patients with solid tumors. Based on the dose-escalation results in patients with NSCLC, Dato-DXd 6 mg/kg intravenously every 3 weeks is being evaluated in patients with advanced/metastatic TNBC and HR+/HER2− breast cancer who relapsed/progressed on standard therapies. Two patients with TNBC received Dato-DXd 8 mg/kg prior to selection of 6 mg/kg for dose expansion. Safety and efficacy were assessed, including objective response rate (ORR) per RECIST version 1.1 by blinded independent central review (BICR). Results: As of the April 6, 2021, data cutoff, 43 patients with TNBC had received ≥1 dose of Dato-DXd, with 27 patients (63%) continuing and 16 patients (37%) discontinuing treatment all due to disease progression. The median age was 53 years (range, 32-82 years). Forty-one patients (95%) had received ≥2 prior lines of therapy; 19 patients (44%) had received prior immunotherapy and 7 (16%) had received prior sacituzumab govitecan. The median duration of treatment was 2.8 months (range, 0.7-6.9 months). The median follow-up was 3.9 months (range, 0.3-9.2 months). Among 38 patients evaluable for response, the ORR by BICR was 39% (15 partial responses [PR]), with 12 confirmed and 3 pending confirmation. The disease control rate was 84% (32/38). The median time to response was 1.35 months (1.2-3.2 months) for the 12 confirmed PRs. All-cause treatment-emergent adverse events (TEAEs; any grade, grade ≥3) were observed in 95% and 35% of patients, respectively; 2 events were grade 4 and 0 grade 5. The most common TEAEs (any grade [≥30%], grade ≥3) included nausea (58%, 0%), stomatitis (53%, 9%), alopecia (35%, N/A), vomiting (35%, 2%), and fatigue (33%, 7%). One patient had grade 3 decreased neutrophil count; no cases of grade ≥3 diarrhea were observed. No cases of treatment-related interstitial lung disease as adjudicated by an independent committee were reported. Serious TEAEs were observed in 5 patients (12%); no TEAEs were associated with death. Dose reductions occurred in 9 patients due to stomatitis, fatigue, mucosal inflammation, dry eye, retinal exudates, and blurred vision (multiple counts per TEAE). Three patients had dose interruptions due to stomatitis, mucosal inflammation, bronchitis, and musculoskeletal chest pain. No patients discontinued treatment due to adverse events. Conclusions: Preliminary results showed that Dato-DXd demonstrates promising antitumor activity with a manageable safety profile in patients with previously treated advanced/metastatic TNBC; confirmatory studies in patients with breast cancer are warranted. Citation Format: Ian Krop, Dejan Juric, Toshio Shimizu, Anthony Tolcher, Alexander Spira, Toru Mukohara, Aaron E. Lisberg, Takahiro Kogawa, Kyriakos P. Papadopoulos, Erika Hamilton, Senthil Damodaran, Jonathan Greenberg, Wen Gu, Fumiaki Kobayashi, Ferdinand Guevara, Takahiro Jikoh, Yui Kawasaki, Funda Meric-Bernstam, Aditya Bardia. Datopotamab deruxtecan in advanced/metastatic HER2- breast cancer: Results from the phase 1 TROPION-PanTumor01 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-05.