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Purpose: SYNB1891 is a live, modified strain of the probiotic Escherichia coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia, leading to STimulator of INterferon Genes (STING) activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways. Patients and Methods: This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral injections of SYNB1891 either alone or in combination with atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens. Results: Twenty-four participants received monotherapy across six cohorts, and 8 participants received combination therapy in two cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24 hours after the first intratumoral dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of IFN-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained predose and 7 days following the third weekly dose. In addition, a dose-related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies. Conclusions: Repeat intratumoral injection of SYNB1891 as monotherapy and in combination with atezolizumab was safe and well tolerated, and evidence of STING pathway target engagement was observed.

Summary In a retrospective analysis of patients with unresectable melanoma, higher pretreatment tissue densities of CD16+ macrophages were associated with clinical benefit from combined CTLA-4 and PD-1 blockade. With further validation, this biomarker could serve as a tool in selecting between immune checkpoint inhibitor regimens. See related article by Lee et al., p. xxxx

Thoracic stereotactic body radiation therapy (SBRT) is associated with high rates of local control but carries a risk of pneumonitis. Immunotherapy is a standard treatment for patients with metastatic disease but can also cause pneumonitis. To evaluate the feasibility and safety of thoracic SBRT with systemic immunotherapy, clinical outcomes of patients treated with immune checkpoint blockade (ICB) and SBRT on prospective trials were reviewed.Three consecutive phase 1 trials of combination SBRT and ICB conducted between 2016 to 2020 for widely metastatic solid tumors were reviewed. The protocols mandated adherence to NRG BR001/BR002 organs at risk constraints, resulting in100% coverage of some target volumes. ICB was administered either sequentially (within 7 days after completion of SBRT) or concurrently (before or at the start of SBRT), depending on protocol. End points included pneumonitis, dose-volume constraints, local failure, and overall survival. The cumulative incidence estimator and Kaplan-Meier method were used.In the study, 123 patients met eligibility with 311 metastases irradiated. The most common histologies included non-small cell lung cancer (33%) and colorectal cancer (12%). Median follow-up was 12 months. The overall rate of grade 3+ pneumonitis was 8.1%; 1-year local failure was 3.6%. Established dosimetric parameters were significantly associated with the development of pneumonitis (P.05). In most patients, the lungs were not challenged with high doses of radiation, defined as receiving ≥75% of the maximum for a given lung dose-volume constraint. Patients who were challenged were not found to have a significantly higher risk of pneumonitis.In the largest series of thoracic SBRT and immunotherapy, local control was excellent with acceptable toxicity and support the conclusion that established dose-volume constraints for the lung are safe. However, these results highlight the potential value in reporting of organs at risk being challenged with doses approaching protocol specified limits.

Adjuvant pembrolizumab significantly improved recurrence-free survival (RFS) versus placebo in resected stage IIB and IIC melanoma in the phase 3 KEYNOTE-716 study. Health-related quality of life (HRQoL) results are reported.Patients were randomly assigned 1:1 to pembrolizumab 200 mg (2 mg/kg, patients ≥12 to18 years) Q3W or placebo for ≤17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. Change from baseline in EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) was a prespecified exploratory end point. Change in EORTC QLQ-C30 functioning, symptom, and single-item scales, and EQ-5D-5L visual analog scale (VAS) were also summarized. Primary analyses were performed at week 48 to ensure adequate completion/compliance. The HRQoL population comprised patients who received ≥1 dose of treatment and completed ≥1 assessment.The HRQoL population included 969 patients (pembrolizumab, n = 483; placebo, n = 486). Compliance at week 48 was ≥80% for both instruments. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores were stable from baseline to week 48 in both arms, with no clinically meaningful decline observed. Scores did not differ significantly between pembrolizumab and placebo. EORTC QLQ-C30 GHS/QoL, physical functioning, role functioning, and EQ-5D-5L VAS scores remained stable through week 96 in both arms.HRQoL was stable with adjuvant pembrolizumab, with no clinically meaningful decline observed. Change from baseline in HRQoL was similar between arms. These results, in conjunction with the improved RFS and manageable safety previously reported, support the use of adjuvant pembrolizumab for high-risk stage II melanoma.

Background Indoleamine 2,3-dioxygenase 1 (IDO1), an interferon-inducible enzyme, contributes to tumor immune intolerance. Immune checkpoint inhibition may increase interferon levels; combining IDO1 inhibition with immune checkpoint blockade represents an attractive strategy. Epigenetic agents trigger interferon responses and may serve as an immunotherapy priming method. We evaluated whether epigenetic therapy plus IDO1 inhibition and immune checkpoint blockade confers clinical benefit to patients with advanced solid tumors. Methods ECHO-206 was a Phase I/II study where treatment-experienced patients with advanced solid tumors (N = 70) received azacitidine plus an immunotherapy doublet (epacadostat [IDO1 inhibitor] and pembrolizumab). Sequencing of treatment was also assessed. Primary endpoints were safety/tolerability (Phase I), maximum tolerated dose (MTD) or pharmacologically active dose (PAD; Phase I), and investigator-assessed objective response rate (ORR; Phase II). Results In Phase I, no dose-limiting toxicities were reported, the MTD was not reached; a PAD was not determined. ORR was 5.7%, with four partial responses. The most common treatment-related adverse events (AEs) were fatigue (42.9%) and nausea (42.9%). Twelve (17.1%) patients experienced ≥1 fatal AE, one of which (asthenia) was treatment-related. Conclusions Although the azacitidine-epacadostat-pembrolizumab regimen was well tolerated, it was not associated with substantial clinical response in patients with advanced solid tumors previously exposed to immunotherapy.

Summary Myeloid-derived suppressor cells (MDSC) are associated with resistance to anti-PD-1 therapies. All-trans retinoic acid (ATRA) may induce maturation of MDSCs and alter their immunosuppressive effects. Adding ATRA to pembrolizumab may target this resistance mechanism to enhance the overall impact of anti-PD-1–based immunotherapy. See related article by Tobin et al., p. 1209

PURPOSEThis phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).METHODSIn this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017.RESULTSBetween March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.CONCLUSIONUsing a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.

Supplemental Figure 3. Serum cytokine levels in subjects receiving SYNB1891

Supplemental Table 2. Tumor types and characteristics for Nanostring and immunofluorescence data analysis

Purpose:SYNB1891 is a live, modified strain of the probiotic Escherichia coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia, leading to STimulator of INterferon Genes (STING) activation in phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways.Patients and Methods:This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral injections of SYNB1891 either alone or in combination with atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens.Results:Twenty-four participants received monotherapy across six cohorts, and 8 participants received combination therapy in two cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24 hours after the first intratumoral dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of IFN-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained predose and 7 days following the third weekly dose. In addition, a dose-related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies.Conclusions:Repeat intratumoral injection of SYNB1891 as monotherapy and in combination with atezolizumab was safe and well tolerated, and evidence of STING pathway target engagement was observed.

Purpose:This phase I study assessed the safety, pharmacokinetics (PKs), and efficacy of MIW815 (ADU-S100), a novel synthetic cyclic dinucleotide that activates the stimulator of IFN genes (STING) pathway, in patients with advanced/metastatic cancers.Patients and Methods:Patients (n = 47) received weekly i.t. injections of MIW815, 50 to 6,400 μg, on a 3-weeks-on/1-week-off schedule.Results:A maximum tolerated dose was not reached. Most common treatment-related adverse events were pyrexia (17%), chills, and injection-site pain (each 15%). MIW815 was rapidly absorbed from the injection site with dose-proportional PK, a rapid terminal plasma half-life (approximately 24 minutes), and high interindividual variability. One patient had a partial response (PR; Merkel cell carcinoma); two patients had unconfirmed PR (parotid cancer, myxofibrosarcoma). Lesion size was stable or decreased in 94% of evaluable, injected lesions. RNA expression and immune infiltration assessments in paired tumor biopsies did not reveal significant on-treatment changes. However, increases in inflammatory cytokines and peripheral blood T-cell clonal expansion suggested systemic immune activation.Conclusions:MIW815 was well tolerated in patients with advanced/metastatic cancers. Clinical activity of single-agent MIW815 was limited in this first-in-human study; however, evidence of systemic immune activation was seen.

Immunohistochemistry of injected and noninjected lesions

Supplementary tables and figure legends

List of TCGA samples included in this study.

Supplementary Table 1 shows the adverse events suspected to be study drug-related. Supplementary Table 2 shows the sequencing data availability by treatment group. Supplementary Table 3 shows the observed correlations between selected mutations/alterations. Supplementary Figure 1 shows the time on study for each patient. Supplementary Figure 2 shows the gene alterations ordered by chromosome and PFS. Supplementary Figure 3 shows gene alterations ordered by chromosome and percentage change from baseline. Supplementary Figure 4 shows Kaplan-Meier plot of PFS for patients with or without a GNAQ mutation.

Supplementary Figure 1: Post-progresion survival based on initial PFS (6, 9, 12, and 15 months). Supplementary Figure 2: Radiographic example of isolated progression in one patient with acquired resistance to anti-PD-1. Supplementary Figure 3: Overall survival in the entire cohort

Up to 50% of patients with uveal melanoma (UM) develop metastatic disease, for which there is no effective systemic treatment. This study aimed to evaluate the safety and efficacy of the orally available protein kinase C inhibitor, AEB071, in patients with metastatic UM, and to perform genomic profiling of metastatic tumor samples, with the aim to propose combination therapies. Patients with metastatic UM (n = 153) were treated with AEB071 in a phase I, single-arm study. Patients received total daily doses of AEB071 ranging from 450 to 1,400 mg. First-cycle dose-limiting toxicities were observed in 13 patients (13%). These were most commonly gastrointestinal system toxicities and were dose related, occurring at doses ≥700 mg/day. Preliminary clinical activity was observed, with 3% of patients achieving a partial response and 50% with stable disease (median duration 15 weeks). High-depth, targeted next-generation DNA sequencing was performed on 89 metastatic tumor biopsy samples. Mutations previously identified in UM were observed, including mutations in GNAQ, GNA11, BAP1, SF3B1, PLCB4, and amplification of chromosome arm 8q. GNAQ/GNA11 mutations were observed at a similar frequency (93%) as previously reported, confirming a therapeutic window for inhibition of the downstream effector PKC in metastatic UM.In conclusion, the protein kinase C inhibitor AEB071 was well tolerated, and modest clinical activity was observed in metastatic UM. The genomic findings were consistent with previous reports in primary UM. Together, our data allow envisaging combination therapies of protein kinase C inhibitors with other compounds in metastatic UM.

List of 1,015 genes used for identification of T cell-inflamed, intermediate, and non-T cell-inflamed tumor subtypes.

List of UTSW KCP patients with RNA-Seq and exome-seq. Sheet 1 contains information of 35 patients whose matched trio RNA-Seq data were used in the primary DisHet analyses. Sheet 2 contains information of patients whose bulk tumors were analyzed by RNA-Seq and whose follow up data are available. There are overlap between patients from these two sheets. Sheet 3 contains the information of tumorgraft data used in Fig. 5bc.

The full technical details of DisHet

Annotation of eTME genes. eTME genes (3x) are shown in the table. The "eTME (20x)" column shows eTME genes that satisfy the 20x cutoff. The other columns show the interpretation of the eTME genes using BLUEPRINT data, the Winslow signatures, Immunome signatures, and the ESTIMATE signature (immune and stromal signatures combined).

By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, TH1 cells, neutrophils, macrophages, B cells, and CD8+ T cells. IS is enriched for aggressive RCCs, including BAP1-deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors.Significance: We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. Cancer Discov; 8(9); 1142–55. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10.Significance:In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response.See related commentary by Sullivan, p. 2960.This article is highlighted in the In This Issue feature, p. 2945

Anti–Programed Death 1 (PD-1) is standard immunotherapy for multiple cancers, and the expression of one of its ligands, PD-L1, has been described in germ cell tumors (GCT). Neither the clinical activity of anti–PD-1 nor the incidence of an immunoresponsive tumor microenvironment has been described for GCTs. A patient initially diagnosed with melanoma via fine needle aspiration was treated with one dose of antibody to PD-1. A core needle biopsy was subsequently performed to acquire sufficient tissue for molecular analysis, which led to a change in diagnosis to metastatic embryonal carcinoma. The testicular GCT cohort of The Cancer Genome Atlas was analyzed using a T-cell gene signature associated with benefit from immunotherapy. Primary tumors (N = 134) were categorized as high (T-cell–inflamed), medium, or low (non–T-cell-inflamed) by their T-cell signature derived from RNAseq data. Anti–PD-1 induced decreases in serum markers and a 33% reduction in tumor volume. Gene expression revealed a T-cell–inflamed tumor microenvironment in 47% of testicular GCTs, including seminoma (83%) and nonseminoma (17%) tumor subtypes. Expression of alpha-fetoprotein (AFP) RNA correlated with lack of the T-cell signature, with increasing AFP RNA inversely correlating with the inflamed signature and expression of IFNγ-associated genes. These data suggest that GCTs can respond to anti–PD-1 and that gene expression profiling supports investigation of immunotherapy for treatment of GCTs. Cancer Immunol Res; 4(11); 903–9. ©2016 AACR.

Anti–PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti–PD-1. We retrospectively reviewed 488 patients treated with anti–PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3–32.8 months). Most progression was isolated (78% of patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median PPS was 12.8 months (range 0.1–51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated versus systemic progression exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS ≥ 15 months showed significant PPS improvement (P = 0.036). Two patients experienced subsequent responses to anti–PD-1 resumption. In conclusion, acquired resistance to anti–PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption. Cancer Immunol Res; 5(5); 357–62. ©2017 AACR.

Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity.Significance:This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.See related commentary by Sitkovsky, p. 16.This article is highlighted in the In This Issue feature, p. 1

Gene ontology analysis shows enriched GO terms of the 904 eTME genes (20x cutoff) (first sheet), the 778 and the 610 eTME genes (20x cutoff) that are not captured by the Immunome alone and Immunome+ESTIMATE+Winslow gene signatures (second and third sheets).

Supplemental Appendix

Sup. Fig. 1 Simulation analyses show accurate dissection of bulk tumor RNA-Seq data by DisHet. Sup. Fig. 2 Validating immune/stroma component expression dissected by DisHet. Sup. Fig. 3 Comparison of dissection performance of DeMix and DisHet. Sup. Fig. 4 Principal Component Analysis (PCA) shows the clustering of TCGA pan-RCC patients tumors by the tumor-specific genes and eTME-specific genes, respectively. Sup. Fig. 5 CD4 and CD8 immunohistochemistry staining in the Six2-Cre;VhlF/F;Pbrm1F/F and Six2-Cre;VhlF/F;Bap1F/+. Supl. Fig. 6 Clinical manifestations of eTME-NIS patients.

Significant biological processes (FDR

Supplementary figures 1-6, supplementary tables 1-4

PURPOSE NCI-MATCH is a precision medicine trial using genomic testing to allocate patients with advanced malignancies to targeted treatment subprotocols. This report combines two subprotocols evaluating trametinib, a MEK1/2 inhibitor, in patients with Neurofibromatosis 1 ( NF1[S1] or GNA11/Q [S2]) altered tumors. METHODS Eligible patients had tumors with deleterious inactivating NF1 or GNA11/Q mutations by the customized Oncomine AmpliSeq panel. Prior MEK inhibitor treatment was excluded. Glioblastomas (GBMs) were permitted, including malignancies associated with germline NF1 mutations (S1 only). Trametinib was administered at 2 mg once daily over 28-day cycles until toxicity or disease progression. Primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS) at 6 months, PFS, and overall survival. Exploratory analyses included co-occurring genomic alterations and PTEN loss. RESULTS Fifty patients were eligible and started therapy: 46 with NF1 mutations (S1) and four with GNA11 mutations (S2). In the NF1 cohort, nonsense single-nucleotide variants were identified in 29 and frameshift deletions in 17 tumors. All in S2 had nonuveal melanoma and GNA11 Q209L variant. Two partial responses (PR) were noted in S1, one patient each with advanced lung cancer and GBM for an ORR of 4.3% (90% CI, 0.8 to 13.1). One patient with melanoma in S2 had a PR (ORR, 25%; 90% CI, 1.3 to 75.1). Prolonged stable disease (SD) was also noted in five patients (four in S1 and one in S2) with additional rare histologies. Adverse events were as previously described with trametinib. Comutations in TP53 and PIK3CA were common. CONCLUSION Although these subprotocols did not meet the primary end point for ORR, significant responses or prolonged SD noted in some disease subtypes warrants further investigation.

Purpose:The stimulator of IFN genes (STING) is a transmembrane protein that plays a role in the immune response to tumors. Single-agent STING agonist MIW815 (ADU-S100) has demonstrated immune activation but limited antitumor activity. This phase Ib, multicenter, dose-escalation study assessed the safety and tolerability of MIW815 plus spartalizumab (PDR001), a humanized IgG4 antibody against PD-1, in 106 patients with advanced solid tumors or lymphomas.Patients and Methods:Patients were treated with weekly intratumoral injections of MIW815 (50–3,200 μg) on a 3-weeks-on/1-week-off schedule or once every 4 weeks, plus a fixed dose of spartalizumab (400 mg) intravenously every 4 weeks.Results:Common adverse events were pyrexia (n = 23; 22%), injection site pain (n = 21; 20%), and diarrhea (n = 12; 11%). Overall response rate was 10.4%. The MTD was not reached. Pharmacodynamic biomarker analysis demonstrated on-target activity.Conclusions:The combination of MIW815 and spartalizumab was well tolerated in patients with advanced/metastatic cancers, including in patients with anti-PD-1 refractory disease. Minimal antitumor responses were seen.

Supplementary tables and figures with legends

Supplementary Table S2 shows LRRC15 IHC expression in tumor and stroma of patients with sarcoma treated ABBV-085 monotherapy at 3.6 or 4.2 mg/kg

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Supplementary Table from Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors

Sup Fig 13