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Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment. We hypothesized that cryoablation may modify the immune microenvironment through direct modulation of the tumor, thereby generating an anti-tumor response in tumors refractory to immune checkpoint inhibition (ICI). In this non-randomized phase II single-center study (NCT03290677), subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoints were safety, feasibility and tumor response in non-ablated lesions. From May 2018 through July 2020, 17 patients were treated on study. The study met its primary endpoints with the combination strategy found to be safe and feasible with an objective response rate of 23.5% and disease control rate of 41% (4 partial response, 3 stable disease). Our data support further study of this synergistic therapeutic approach. Most patients with metastatic melanoma still develop primary or acquired resistance to immune checkpoint inhibition (ICI). Here the authors report the results of a phase II trial of cryoablation and ICI in patients with unresectable melanoma progressing on ICI.

Background C ytokine i nduced m emory- l ike natural killer (CIML NK) cells combined with an IL-15 super-agonist (N-803) are a novel modality to treat relapsed/refractory head and neck cancer. Methods We report data from a phase I trial of haploidentical CIML NK cells combined with N-803 with or without ipilimumab (IPI) in relapsed/refractory head and neck cancer patients after a median of 6 prior lines of therapy. The trial adhered to a 3 + 3 dose de-escalation design, with primary endpoint being safety. High-resolution immunophenotypic and transcriptional profiling characterized the NK cells and their interacting partners in vivo. Results The primary safety endpoint was established, with dose-limiting toxicity in 1/10 patients. A transient disease control rate correlated with donor NK cell expansion, the latter occurring irrespective of IPI. The combination of CIML NK cells with N-803 and IPI was associated with increased early NK cell proliferation, contraction of Treg: Tcon, rapid recovery of recipient CD8 + T cells, and subsequent accelerated rejection of donor NK cells. Conclusions CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype. However, the combination leads to reduced HLA mismatched NK cell persistence, resulting in an important limitation affecting NK cell combination therapies in clinical trials. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI. Trial Registration NCT04290546.

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased CLEC9A+ dendritic cell and CLEC7A/SYK expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8 + T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13 + CD8 + T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.

BackgroundTerminally exhausted CD8+ T cells, resulting from chronic antigen exposure in the tumor microenvironment, are defined by loss of effector function, decreased proliferative potential, and are associated with limited response to immune checkpoint blockade (ICB).1 CD38 is an ecto-enzyme, involved in NAD+ catabolism.2 that was shown to be expressed in terminally exhausted CD8+ T cells in melanoma and correlate with lack of response to ICB,3 although its specific role in T cell exhaustion and its therapeutic potential has remained poorly defined.MethodsIn this study we used human CART cells, as well as, tumor infiltrating lymphocytes (TILs) from melanoma patients to study the role of CD38 in T cell exhaustion and dysfunction. Further mechanistic studies were conducted using murine cancer models. We used a set of genetic and pharmacological tools to block CD38, followed by extensive immunophenotyping and T cell effector functions analysis. Lastly, we used a cohort of patient derived biospecimens to test the efficiency of CD38 blockade to overcome clinical resistance to ICB.ResultsWe confirm that CD38 expression is increased in CD8+ T cells during tumor progression and following PD-1 blockade and serves as a predictive marker of ICB resistance in multiple cancers. CD38 expressing T cells have impaired effector functions and inferior metabolic potential, testes using MS-LC metabolomics and mitochondrial function analysis. CD38 blockade using genetic or pharmacological tools results in improved cytotoxic function, increased proliferation and an increase in T cell memory genes which were shown to induce durable responses to ICB.3 Importantly, dual blockade of PD-1 (pembrolizumab) and CD38 (daratumumab) in a cohort of patient-derived organotypic tumor spheroids (PDOTS)4 5 of patients with cutaneous melanoma and other cancers (n=35) show dramatic response to ICB (54% of the tumors), as opposed to each treatment alone (αPD-1 11%, αCD38 22.5%). Combinatorial therapy not only enhanced tumor cytotoxicity in treatment naïve tumors but was also able to overcome ICB resistance in clinically resistant refractory melanoma (10/18, 55%) and in murine mouse models in a NAD+ and CD8+ dependent manner, consistent with the role of CD38 in NAD+ catabolism.ConclusionsTaken together, these data (figure 1) confirm a role for the CD38/NAD+ axis in T cell dysfunction and its association with ICB resistance and support further pre-clinical and clinical development of CD38-directed strategy to overcome ICB resistance.ReferencesBlank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 2019;19, 665–674.Piedra-Quintero, Z. L., Wilson, Z., Nava, P. & Guerau-de-Arellano, M. CD38: An Immunomodulatory Molecule in Inflammation and Autoimmunity. Front. Immunol. 2020; 11, 597959.Sade-Feldman, M. et al. Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2019;176, 404.Aref, A. R. et al. 3D microfluidic ex vivo culture of organotypic tumor spheroids to model immune checkpoint blockade. Lab Chip 2018;18, 3129–3143.Jenkins, R. W. et al. Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov. 2018;8: 196–215.Ethics ApprovalThe Office for Human Research Studies (OHRS), Dana-Farber/Harvard Cancer Center, Massachusetts General Hospital (MGH).IRB protocol number: 11–181Abstract 561 Figure 1

The potent immunostimulatory effects of toll-like receptor 8 (TLR8) agonism in combination with PD-1 blockade have resulted in various preclinical investigations, yet the mechanism of action in humans remains unknown. To decipher the combinatory mode of action of TLR8 agonism and PD-1 blockade, we employed a unique, open-label, phase 1b pre-operative window of opportunity clinical trial (NCT03906526) in head and neck squamous cell carcinoma (HNSCC) patients. Matched pre- and post-treatment tumor biopsies from the same lesion were obtained. We used single-cell RNA sequencing and custom multiplex staining to leverage the unique advantage of same-lesion longitudinal sampling. Patients receiving dual TLR8 agonism and anti-PD-1 blockade exhibited marked upregulation of innate immune effector genes and cytokines, highlighted by increased dendritic cell and expression. This was revealed via comparison with a previous cohort from an anti-PD-1 blockade monotherapy single-cell RNA sequencing study. Furthermore, in dual therapy patients, post-treatment mature dendritic cells increased in adjacency to CD8 T-cells. Increased tumoral cytotoxic T-lymphocyte densities and expanded CXCL13 CD8 T-cell populations were observed in responders, with increased tertiary lymphoid structures (TLSs) across all three patients. This study provides key insights into the mode of action of TLR8 agonism and anti-PD-1 blockade immune targeting in HNSCC patients.

Tumor-infiltrating lymphocyte (TIL) therapy is FDA-approved for patients with treatment-resistant advanced melanoma, but the TIL subpopulations critical for tumor eradication remains incompletely understood. Using patient-derived TIL-melanoma co-cultures, we identified and characterized a novel subset of CD8 TIL, capable of class I HLA-independent cancer cell lysis. The lymphotoxin β receptor (LTβR) and interferon (IFN) sensing pathways were nominated as key determinants of TIL-mediated cancer cell killing from a whole-genome, loss-of-function CRISPR screen. Validation studies confirmed that dual LTβR and IFN sensing is necessary and sufficient for cancer cell lysis, and that expanded CD8 TIL express high lymphotoxin β ( ) and upregulate lymphotoxin α ( ) upon coculture with cancer cells. Leveraging paired scRNA-seq and scTCR-seq data, we confirmed that enrichment of T cells is associated with clinical response to TIL, and that TIL are expanded from putative neoantigen-reactive, CD8 T cells in resected tumors.

Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors of a wide-range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed , an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NFκB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NFκB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription factor activity.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.Competing Interest StatementR.W.J. is a member of the advisory board for and has a financial interest in Xsphera Biosciences Inc. a company focused on using ex vivo profiling technology to deliver functional, precision immune-oncology solutions for patients, providers, and drug development companies. R.W.J. has received honoraria from Incyte (invited speaker), G1 Therapeutics (advisory board), Bioxcel Therapeutics (invited speaker). R.W.J. has ownership interest in U.S. patents US20200399573A9 and US20210363595A1. R.W.J.'s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. A.M has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, ManaT Bio, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is currently a part-time Entrepreneur in Residence at Third Rock Ventures, is an equity holder in ManaT Bio, Asher Biotherapeutics and Abata Therapeutics, and has received research funding support from Bristol-Myers Squibb. A.Ms interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. J.M.S., L-C.C, N.S, M.M., N.N., R.S. are current employees with Teiko.bio and own stock. E.E. and S.A.E. were employed with Teiko.bio in the past 2 years and own stock. R.S. and M.H.S. are Teiko.bios co-founders and R.S. serves on the company board. M.H.S. serves as an advisor for Teiko.bio and owns stock. M.E.W. worked as a contractor for Teiko.bio during this project. M.H.S. has received a speaking honorarium from Standard BioTools and Kumquat Bio, has been a paid consultant for Five Prime, Ono, January, Earli, Astellas, and Indaptus, and has received research funding from Roche/Genentech, Pfizer, Valitor, and Bristol Myers Squibb. X.W. and C.R.F. report a patent on the B7-H3 CAR T cells (US10519214B2). K.T.F. serves on the Board of Directors of Clovis Oncology, Strata Oncology, Kinnate, and Scorpion Therapeutics; Scientific Advisory Boards of PIC Therapeutics, Apricity, C-Reveal, Tvardi, ALX Oncology, xCures, Monopteros, Vibliome, Karkinos, Soley Therapeutics, Alterome, Immagene, and intrECate; consultant to Nextech, Takeda, Novartis, Transcode Therapeutics, and Roche/Genentech. R.T.M. consults for Bristol Myers Squibb. G.M.B. has sponsored research agreements through her institution with: Olink Proteomics, Teiko Bio, InterVenn Biosciences, and Palleon Pharmaceuticals. She has served on advisory boards for: Iovance, Merck, Nektar Therapeutics, Novartis, and Ankyra Therapeutics. She consults for: Merck, InterVenn Biosciences, Iovance, and Ankyra Therapeutics. She holds equity in Ankyra Therapeutics. M.S.F received funding from Calico Life Sciences, Bristol-Myers Squibb, Istari Oncology and served as a consultant for Galvanize Therapeutics. N.H. holds equity in BioNTech and is an advisor for Related Sciences/Danger Bio, Repertoire Immune Medicines and CytoReason, and receives research funding from Calico Life Sciences and Bristol-Myers Squibb. D.L. serves on the scientific advisory board for Oncovalent Therapeutics, and received honorariums from Genentech.Footnotes* change to conflict of interest and one typo in author name