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Neoantigens arise from mutations in cancer cells and are important targets of T cell-mediated anti-tumor immunity. Here, we report the first open-label, phase Ib clinical trial of a personalized neoantigen-based vaccine, NEO-PV-01, in combination with PD-1 blockade in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. This analysis of 82 patients demonstrated that the regimen was safe, with no treatment-related serious adverse events observed. De novo neoantigen-specific CD4 + and CD8 + T cell responses were observed post-vaccination in all of the patients. The vaccine-induced T cells had a cytotoxic phenotype and were capable of trafficking to the tumor and mediating cell killing. In addition, epitope spread to neoantigens not included in the vaccine was detected post-vaccination. These data support the safety and immunogenicity of this regimen in patients with advanced solid tumors (Clinicaltrials.gov: NCT02897765)., Competing Interests: Declaration of Interests P.A.O.: research funding paid to the institution—Bristol-Myers Squibb, Merck, AstraZeneca, Celldex, CytomX, GlaxoSmithKline, ARMO Biosciences, Neon Therapeutics; consultant—Array, Bristol-Myers Squibb, Merck, Genentech, Pfizer, Novartis, Neon Therapeutics, CytomX, Celldex. S.H.-L.: consultant—Amgen, Bristol-Myers Squibb, Genmab, Xencor; research support—Bristol-Myers Squibb, Merck, and Vaccinex. B.C.: member of the speakers’ bureaus for Regeneron and Sanofi. R.G.: advisory board member—Achilles; consultant—Horizon Pharma (spouse), GenePlus. A.N.: research funding from NCI, EMD Serono, MedImmune, Healios Oncology Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol-Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, and Immune Deficiency Foundation (spouse); advisory board member—CytomX Therapeutics, Novartis, Kymab, and Genome; travel and accommodation expense—ARMO BioSciences. N.B.: scientific advisory board member—Checkpoint Sciences, Curevac, Primevax, Novartis, Avidea, BI, Rome Therapeutics, Neon Therapeutics, Roche, and Genentech. Extramural member of the Parker Institute for Cancer Immunotherapy K.M.: advisory boards or consultant—Nektar, ImaginAb, Neoleukin, and Akrevia; DSMB—IOvance. M.M.A.: research grants—Genentech, Bristol-Myers Squibb, AstraZeneca, Lilly; consultant—Genentech, Bristol-Myers Squibb, AstraZeneca, Merck, Maverick, Blueprint Medicine, Syndax, Ariad, Nektar, Gritstone, and Neon Therapeutics M.D.H.: research funding—Bristol-Myers Squibb; consultant—Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Blueprint, Immunai, and Shattuck Labs; travel support/honoraria—AstraZeneca, Eli Lilly, Merck, and Bristol-Myers Squibb; and a patent has been filed by MSK related to the use of tumor mutation burden to predict the response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. J.J.L.: honoraria/consultant—Pfizer, C4 Therapeutics, Nuvalent, and Genentech; institutional research funding—Neon, Hengrui Therapeutics, Turning Point Therapeutics, and Novartis; travel fees—Pfizer; CME funding—OncLive. T.F.: research funding—Janssen; research funding to the institute—Seattle Genetics, Incyte, Bristol-Myers Squibb, Neon Therapeutics, and Roche/Genentech. R.B.G.: board of directors—Alkermes plc and Infinity Pharmaceuticals; scientific advisory board—Leap Therapeutics; stockholder and employee—Neon Therapeutics/BioNTech US. Stockholder and either current or past employees of Neon Therapeutics/BioNTech US: M.E.B., K.N.B., T.E.S., V.K., S.J.T., R.B., R.R.C., B.T., J.S., A.P., D.H., D.B., Y.S.T., J.Z.D., Y.W., Y.H., Z.H., A.W., L.D.C., M.A.M., K.M., J.G., Z.S.K., M.S.R., M.D., E.F., and L.S., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Adequate organ function and good performance status (PS) are common eligibility criteria for phase I trials. As inflammation is pathogenic and prognostic in cancer we investigated the prognostic performance of inflammation-based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR)., Methods: We studied inflammatory scores in 118 unselected referrals. NLR normalization was recalculated at disease reassessment. Each variable was assessed for progression-free (PFS) and overall survival (OS) on uni- and multivariate analyses and tested for 90 days survival (90DS) prediction using receiving operator curves (ROC)., Results: We included 118 patients with median OS 4.4 months, 23% PS>1. LDH≥450 and NLR≥5 were multivariate predictors of OS (p<0.001). NLR normalization predicted for longer OS (p<0.001) and PFS (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under ROC values of 0.66 and 0.64, and OS with c-score of 0.69 and 0.60. The combination of NLR+PS increased prognostic accuracy to 0.72. The NLR was externally validated in a cohort of 126 subjects., Conclusions: We identified the NLR as a validated and objective index to improve patient selection for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months. Prospective validation of the NLR is warranted.

Rat monoclonal anti-idiotype antibodies (mAb2) were raised against two mouse monoclonal antibodies (mAb1), 1D10 and 2A6, with specificity for the M-like protein of Streptococcus equi. The capacity of the mAb2 to inhibit the binding between the corresponding mouse mAb1 against which the mAb2 were raised and the M-like protein was investigated in an inhibition EIA. One of the ten mAb2 examined, namely 5D1 (anti-mAb1 1D10), was able to inhibit this binding. The mAb2 5D1 bound to the mAb1 1D10 in such a way as to completely inhibit the subsequent binding of the M-like protein antigen to the paratope of the mAb1 1D10. The mAb2 5D1 is likely to represent a true image of the M-like protein antigen and may thus be described as an Ab2 beta anti-idiotype antibody.

We have developed an in vivo passive transfer assay using mice to identify monoclonal antibodies (mAbs) which offer protection against Streptococcus equi infection. The assay was developed using serum antibodies collected from horses convalescing from strangles. In this study, we show that a preparation of M-like protein, acid-extracted from S. equi, affords 80% protection to mice immunized with it. A number of mouse mAbs directed against a preparation of M-like protein were then assessed for their ability to passively protect mice against challenge with a lethal dose of the bacteria. Two mAbs, 1D10 and 2A6, were shown to be highly protective. It was also demonstrated, by means of a competitive enzyme immunoassay, that these mAbs recognized different epitopes in the preparation. Examination of a dose-response curve for mAbs 1D10 and 2A6 revealed that optimal levels of protection were achieved using 1 mg of either 1D10 or 2A6, or 0.5 mg 1D10 and 0.5 mg 2A6 given together. Immunological reactivity of these mAbs with a preparation of M-like protein showed that the antigens they recognized were comparable in size to some of the antigens recognized by convalescent horse serum antibodies. The role of immunoglobulin isotype in conferring protection is discussed.