Expanding use of immune‐checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune‐related adverse events (irAE‐N). We evaluate the ...real‐world frequency, phenotypes, co‐occurring immune‐related adverse events (irAEs), and long‐term outcomes of severe, grade III to V irAE‐N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE‐N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE‐N reporting are outlined. ANN NEUROL 2020;87:659–669
The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish ...cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
We measure the two-point clustering of spectroscopically confirmed quasars from the final sample of the Baryon Oscillation Spectroscopic Survey (BOSS) on comoving scales of 4 ≲ s ≲ 22 h
−1 Mpc. The ...sample covers 6950 deg2 ∼ 19 (h
− 1Gpc)3 and, over the redshift range 2.2 ≤ z ≤ 2.8, contains 55 826 homogeneously selected quasars, which is twice as many as in any similar work. We deduce b
Q = 3.54 ± 0.10; the most precise measurement of quasar bias to date at these redshifts. This corresponds to a host halo mass of ∼2 × 1012 h
−1 M⊙ with an implied quasar duty cycle of ∼1 per cent. The real-space projected correlation function is well fitted by a power law of index 2 and correlation length r
0 = (8.12 ± 0.22) h
− 1 Mpc over scales of 4 ≲ r
p ≲ 25 h
−1 Mpc. To better study the evolution of quasar clustering at moderate redshift, we extend the redshift range of our study to z ∼ 3.4 and measure the bias and correlation length of three subsamples over 2.2 ≤ z ≤ 3.4. We find no significant evolution of r
0 or bias over this range, implying that the host halo mass of quasars decreases somewhat with increasing redshift. We find quasar clustering remains similar over a decade in luminosity, contradicting a scenario in which quasar luminosity is monotonically related to halo mass at z ≈ 2.5. Our results are broadly consistent with previous BOSS measurements, but they yield more precise constraints based upon a larger and more uniform data set.
In advanced cancers, transforming growth factor-beta (TGFβ) promotes tumor growth and metastases and suppresses host antitumor immunity. GC1008 is a human anti-TGFβ monoclonal antibody that ...neutralizes all isoforms of TGFβ. Here, the safety and activity of GC1008 was evaluated in patients with advanced malignant melanoma and renal cell carcinoma.
In this multi-center phase I trial, cohorts of patients with previously treated malignant melanoma or renal cell carcinoma received intravenous GC1008 at 0.1, 0.3, 1, 3, 10, or 15 mg/kg on days 0, 28, 42, and 56. Patients achieving at least stable disease were eligible to receive Extended Treatment consisting of 4 doses of GC1008 every 2 weeks for up to 2 additional courses. Pharmacokinetic and exploratory biomarker assessments were performed.
Twenty-nine patients, 28 with malignant melanoma and 1 with renal cell carcinoma, were enrolled and treated, 22 in the dose-escalation part and 7 in a safety cohort expansion. No dose-limiting toxicity was observed, and the maximum dose, 15 mg/kg, was determined to be safe. The development of reversible cutaneous keratoacanthomas/squamous-cell carcinomas (4 patients) and hyperkeratosis was the major adverse event observed. One malignant melanoma patient achieved a partial response, and six had stable disease with a median progression-free survival of 24 weeks for these 7 patients (range, 16.4-44.4 weeks).
GC1008 had no dose-limiting toxicity up to 15 mg/kg. In patients with advanced malignant melanoma and renal cell carcinoma, multiple doses of GC1008 demonstrated acceptable safety and preliminary evidence of antitumor activity, warranting further studies of single agent and combination treatments.
Clinicaltrials.gov NCT00356460.
Summary Background Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit ...with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could improve safety without compromising efficacy. Methods We did this randomised, open-label, phase 2 study at nine academic medical centres in the USA. Eligible patients (aged ≥18 years) with unresectable stage III or IV melanoma (treatment-naive or who had progressed after no more than one previous systemic therapy, with an Eastern Cooperative Oncology Group performance status of 0 or 1) were randomly assigned (1:1) to induction with intravenous nivolumab 3 mg/kg every 2 weeks for six doses followed by a planned switch to intravenous ipilimumab 3 mg/kg every 3 weeks for four doses, or the reverse sequence. Randomisation was done by an independent interactive voice response system with a permuted block schedule (block size four) without stratification factors. After induction, both groups received intravenous nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary endpoint was treatment-related grade 3–5 adverse events until the end of the induction period (week 25), analysed in the as-treated population. Secondary endpoints were the proportion of patients who achieved a response at week 25 and disease progression at weeks 13 and 25. Overall survival was a prespecified exploratory endpoint. This study is registered with ClinicalTrials.gov , number NCT01783938 , and is ongoing but no longer enrolling patients. Findings Between April 30, 2013, and July 21, 2014, 140 patients were enrolled and randomly assigned to nivolumab followed by ipilimumab (n=70) or to the reverse sequence of ipilimumab followed by nivolumab (n=70), of whom 68 and 70 patients, respectively, received at least one dose of study drug and were included in the analyses. The frequencies of treatment-related grade 3–5 adverse events up to week 25 were similar in the nivolumab followed by ipilimumab group (34 50%; 95% CI 37·6–62·4 of 68 patients) and in the ipilimumab followed by nivolumab group (30 43%; 31·1–55·3 of 70 patients). The most common treatment-related grade 3–4 adverse events during the whole study period were colitis (ten 15%) in the nivolumab followed by ipilimumab group vs 14 20% in the reverse sequence group), increased lipase (ten 15% vs 12 17%), and diarrhoea (eight 12% vs five 7%). No treatment-related deaths occurred. The proportion of patients with a response at week 25 was higher with nivolumab followed by ipilimumab than with the reverse sequence (28 41%; 95% CI 29·4–53·8 vs 14 20%; 11·4–31·3). Progression was reported in 26 (38%; 95% CI 26·7–50·8) patients in the nivolumab followed by ipilimumab group and 43 (61%; 49·0–72·8) patients in the reverse sequence group at week 13 and in 26 (38%; 26·7–50·8) and 42 (60%; 47·6–71·5) patients at week 25, respectively. After a median follow-up of 19·8 months (IQR 12·8–25·7), median overall survival was not reached in the nivolumab followed by ipilimumab group (95% CI 23·7–not reached), whereas over a median follow-up of 14·7 months (IQR 5·6–23·9) in the ipilimumab followed by nivolumab group, median overall survival was 16·9 months (95% CI 9·2–26·5; HR 0·48 95% CI 0·29–0·80). A higher proportion of patients in the nivolumab followed by ipilimumab group achieved 12-month overall survival than in the ipilimumab followed by nivolumab group (76%; 95% CI 64–85 vs 54%; 42–65). Interpretation Nivolumab followed by ipilimumab appears to be a more clinically beneficial option compared with the reverse sequence, albeit with a higher frequency of adverse events. Funding Bristol-Myers Squibb.
Myocarditis is an uncommon, but potentially fatal, toxicity of immune checkpoint inhibitors (ICI). Myocarditis after ICI has not been well characterized.
The authors sought to understand the ...presentation and clinical course of ICI-associated myocarditis.
After observation of sporadic ICI-associated myocarditis cases, the authors created a multicenter registry with 8 sites. From November 2013 to July 2017, there were 35 patients with ICI-associated myocarditis, who were compared to a random sample of 105 ICI-treated patients without myocarditis. Covariates of interest were extracted from medical records including the occurrence of major adverse cardiac events (MACE), defined as the composite of cardiovascular death, cardiogenic shock, cardiac arrest, and hemodynamically significant complete heart block.
The prevalence of myocarditis was 1.14% with a median time of onset of 34 days after starting ICI (interquartile range: 21 to 75 days). Cases were 65 ± 13 years of age, 29% were female, and 54% had no other immune-related side effects. Relative to controls, combination ICI (34% vs. 2%; p < 0.001) and diabetes (34% vs. 13%; p = 0.01) were more common in cases. Over 102 days (interquartile range: 62 to 214 days) of median follow-up, 16 (46%) developed MACE; 38% of MACE occurred with normal ejection fraction. There was a 4-fold increased risk of MACE with troponin T of ≥1.5 ng/ml (hazard ratio: 4.0; 95% confidence interval: 1.5 to 10.9; p = 0.003). Steroids were administered in 89%, and lower steroids doses were associated with higher residual troponin and higher MACE rates.
Myocarditis after ICI therapy may be more common than appreciated, occurs early after starting treatment, has a malignant course, and responds to higher steroid doses.
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We present an anisotropic analysis of the baryon acoustic oscillation (BAO) scale in the twelfth and final data release of the Baryon Oscillation Spectroscopic Survey (BOSS). We independently analyse ...the LOWZ and CMASS galaxy samples: the LOWZ sample contains 361 762 galaxies with an effective redshift of z
LOWZ = 0.32; the CMASS sample consists of 777 202 galaxies with an effective redshift of z
CMASS = 0.57. We extract the BAO peak position from the monopole power-spectrum moment, α0, and from the μ2 moment, α2, where μ is the cosine of the angle to the line of sight. The μ2-moment provides equivalent information to that available in the quadrupole but is simpler to analyse. After applying a reconstruction algorithm to reduce the BAO suppression by bulk motions, we measure the BAO peak position in the monopole and μ2-moment, which are related to radial and angular shifts in scale. We report H(z
LOWZ)r
s(z
d) = (11.60 ± 0.60) × 103 km s−1 and D
A(z
LOWZ)/r
s(z
d) = 6.66 ± 0.16 with a cross-correlation coefficient of
$r_{HD_{\rm A}}=0.41$
, for the LOWZ sample; and H(z
CMASS)r
s(z
d) = (14.56 ± 0.37) × 103 km s−1 and D
A(z
CMASS)/r
s(z
d) = 9.42 ± 0.13 with a cross-correlation coefficient of
$r_{HD_{\rm A}}=0.47$
, for the CMASS sample. We demonstrate that our results are not affected by the fiducial cosmology assumed for the analysis. We combine these results with the measurements of the BAO peak position in the monopole and quadrupole correlation function of the same data set (Cuesta et al. 2016, companion paper) and report the consensus values: H(z
LOWZ)r
s(z
d) = (11.63 ± 0.69) × 103 km s−1 and D
A(z
LOWZ)/r
s(z
d) = 6.67 ± 0.15 with
$r_{HD_{\rm A}}=0.35$
for the LOWZ sample; H(z
CMASS)r
s(z
d) = (14.67 ± 0.42) × 103 km s−1 and D
A(z
CMASS)/r
s(z
d) = 9.47 ± 0.12 with
$r_{HD_{\rm A}}=0.52$
for the CMASS sample.
We present distance scale measurements from the baryon acoustic oscillation signal in the constant stellar mass and low-redshift sample samples from the Data Release 12 of the Baryon Oscillation ...Spectroscopic Survey. The total volume probed is 14.5 Gpc3, a 10 per cent increment from Data Release 11. From an analysis of the spherically averaged correlation function, we infer a distance to z = 0.57 of
$D_V(z)r^{\rm fid}_{\rm d}/r_{\rm d} = 2028\pm 21$
Mpc and a distance to z = 0.32 of
$D_V(z)r^{\rm fid}_{\rm d}/r_{\rm d} = 1264\pm 22$
Mpc assuming a cosmology in which
$r^{\rm fid}_{\rm d} = 147.10$
Mpc. From the anisotropic analysis, we find an angular diameter distance to z = 0.57 of
$D_{\rm A}(z)r^{\rm fid}_{\rm d}/r_{\rm d} = 1401\pm 21$
Mpc and a distance to z = 0.32 of 981 ± 20 Mpc, a 1.5 and 2.0 per cent measurement, respectively. The Hubble parameter at z = 0.57 is
$H(z)r_{\rm d}/r^{\rm fid}_{\rm d} = 100.3\pm 3.7$
km s−1 Mpc−1 and its value at z = 0.32 is 79.2 ± 5.6 km s−1 Mpc−1, a 3.7 and 7.1 per cent measurement, respectively. These cosmic distance scale constraints are in excellent agreement with a Λ cold dark matter model with cosmological parameters released by the recent Planck 2015 results.
A subset of patients with metastatic melanoma have sustained remissions following treatment with immune checkpoint inhibitors. However, analyses of pretreatment tumor biopsies for markers predictive ...of response, including PD-1 ligand (PD-L1) expression and mutational burden, are insufficiently precise to guide treatment selection, and clinical radiographic evidence of response on therapy may be delayed, leading to some patients receiving potentially ineffective but toxic therapy. Here, we developed a molecular signature of melanoma circulating tumor cells (CTCs) to quantify early tumor response using blood-based monitoring. A quantitative 19-gene digital RNA signature (CTC score) applied to microfluidically enriched CTCs robustly distinguishes melanoma cells, within a background of blood cells in reconstituted and in patient-derived (n = 42) blood specimens. In a prospective cohort of 49 patients treated with immune checkpoint inhibitors, a decrease in CTC score within 7 weeks of therapy correlates with marked improvement in progression-free survival hazard ratio (HR), 0.17; P = 0.008 and overall survival (HR, 0.12; P = 0.04). Thus, digital quantitation of melanoma CTC-derived transcripts enables serial noninvasive monitoring of tumor burden, supporting the rational application of immune checkpoint inhibition therapies.
OBJECTIVETo describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs).
METHODSPatients with ICI-related neuropathy (irNeuropathy) were ...identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents.
RESULTSWe identified 19 patients with irNeuropathies. ICIs included anti-programmed death–1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy.
CONCLUSIONNeuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.
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