Immunotherapy of cancer is now an essential pillar of treatment for patients with many individual tumor types. Novel immune targets and technical advances are driving a rapid exploration of new treatment strategies incorporating immune agents in cancer clinical practice. Immunotherapies perturb a complex system of interactions among genomically unstable tumor cells, diverse cells within the tumor microenvironment including the systemic adaptive and innate immune cells. The drive to develop increasingly effective immunotherapy regimens is tempered by the risk of immune-related adverse events. Evidence-based biomarkers that measure the potential for therapeutic response and/or toxicity are critical to guide optimal patient care and contextualize the results of immunotherapy clinical trials. Responding to the lack of guidance on biomarker testing in early-phase immunotherapy clinical trials, we propose a definition and listing of essential biomarkers recommended for inclusion in all such protocols. These recommendations are based on consensus provided by the Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Network (SCION) faculty with input from the SITC Pathology and Biomarker Committees and the Journal for ImmunoTherapy of Cancer readership. A consensus-based selection of essential biomarkers was conducted using a Delphi survey of SCION faculty. Regular updates to these recommendations are planned. The inaugural list of essential biomarkers includes complete blood count with differential to generate a neutrophil-to-lymphocyte ratio or systemic immune-inflammation index, serum lactate dehydrogenase and albumin, programmed death-ligand 1 immunohistochemistry, microsatellite stability assessment, and tumor mutational burden. Inclusion of these biomarkers across early-phase immunotherapy clinical trials will capture variation among trials, provide deeper insight into the novel and established therapies, and support improved patient selection and stratification for later-phase clinical trials.

TAC-001 is a novel next-generation antibody-drug conjugate designed for systemic delivery of a potent Toll-like Receptor (TLR)-9 agonist payload. It selectively targets TLR9 to CD22+ B cells, triggering their activation and inducing anti-tumor responses by harnessing the immunological functions of B cells. The mouse surrogate of TAC-001 induced tumor infiltration of activated B cells, effector T cells, and TLS-like structures, leading to sustained anti-tumor activity, including in models resistant to anti-PD-1 therapy. This Phase 1 trial (INCLINE 101; NCT05399654) evaluated the safety, tolerability, pharmacokinetics (PK), immunogenicity, tumor biopsy pharmacodynamic (PD) effects, and preliminary efficacy of TAC-001 across multiple solid tumors with ECOG-PS 0-1. Eligible patients (pts; ≥18 years) received TAC-001 IV Q2W at 3-fold escalating doses (0.1-12 mg/kg) with monitoring for 28-day dose-limiting toxicities (DLTs). Doses were reduced 2-fold or to the next lower tolerated dose level in the event of DLTs. TAC-001 was evaluated in select tumor types at two doses at and below the maximum tolerable dose (MTD). As of September 11, 2024, 72 heavily pre-treated pts (median age 62, range 37-79) with a median of 6 (range 1 to 12) prior therapies were enrolled in the study, including 52 (72%) PD-(L)1 refractory/resistant pts. Treatment-related adverse events (TRAE) were reported in 66 (92%) pts, with 54 (75%) experiencing mild-moderate (Gr 1-2) events. The most frequent TRAEs included chills (61%), fatigue (35%), and pyrexia (35%). Gr ≥ 3 toxicities occurred in 12 (17%) pts, leading to treatment discontinuation in one pt (1.4%). DLTs occurred at 3 mg/kg (1 pt Gr ≥3 bilirubin and elevated ALT) and 12 mg/kg (1 pt transient Gr 3 transaminitis, and 1 pt Gr ≥3 bilirubin with Gr 4 acute kidney injury). The MTD was established at 6mg/kg, with 3mg/kg and 6mg/kg selected for dose expansion. TAC-001 PK exposures (Cmax and AUC) exhibited dose-dependent increases over the dose range tested. Preliminary PD assessment demonstrated dose-dependent CD22 engagement, with activation of circulating B cells observed across dose levels. Among 68 response-evaluable pts, 24 achieved stable disease (≥2 months), 2 (melanoma and cholangiocarcinoma) had confirmed durable partial responses, and 32 had progressive disease. Final results will be presented at the meeting. TAC-001 showed a favorable safety profile, dose-dependent PK/PD activity, and anti-tumor activity in PD- (L)1 refractory pts. Jason T. Henry, Anna C. Pavlick, Timothy Humphries, Sunnie Kim, Martin Gutierrez, Sarina A. Piha-Paul, Daniel Vaena, Shiraj Sen, Alexander Spira, Guru Sonpavde, Ons Harrabi, Feng Jin, Sangeetha Bollin, Laura QM Chow, Hong I. Wan, Cesar A. Perez. A phase 1/2 trial of TAC-001 (TLR9 agonist-CD22 mAb) in advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT045.

Immunotherapy of cancer is now a mainstay of modern oncologic practise and is being integrated with conventional modalities across clinical settings. The Society for Immunotherapy of Cancer (SITC) has initiated a Clinical Immuno- Oncology Network (SCION), where multidisciplinary teams (including clinical oncologists, scientists/immunologists, biostatisticians, and patient advocates) and early career scholars develop immunotherapy clinical trial protocols during an intensive workshop and Winter School. SCION participants have identified a critical gap in guidance for the prioritization of biomarkers in immunotherapy clinical trials. This commentary proposes an evidence- based consensus review process to generate a prioritized checklist of biomarkers for consideration. We recommend grouping biomarkers into three priority levels based on the strength of evidence, breadth of relevance, and feasibility of testing. Level one biomarkers should have strong evidence to justify inclusion in all immunotherapy trials. Level two biomarkers need early evidence supporting inclusion, dependent on suitable funding and scientific validity. Level three biomarkers are of specific importance for individual trials (eg, evaluating therapeutic targets). We invite feedback from the community on the proposed process and prioritization framework. The SCION faculty will work with the SITC Biomarker and Pathology Committees to publish recommendations emerging from a forthcoming evidence- based consensus review. Leveraging the annual clinical trial workshop, SCION faculty will evaluate emerging data to update recommendations as the field evolves.

Imaging of head and neck cancer at initial staging and as part of post-treatment surveillance is a key component of patient care as it guides treatment strategy and aids determination of prognosis. Head and neck cancer includes a heterogenous group of malignancies encompassing several anatomic sites and histologies, with squamous cell carcinoma the most common. Together this comprises the seventh most common cancer worldwide. At initial staging comprehensive imaging delineating the anatomic extent of the primary site, while also assessing the nodal involvement of the neck is necessary. The treatment of head and neck cancer often includes a combination of surgery, radiation, and chemotherapy. Post-treatment imaging is tailored for the evaluation of treatment response and early detection of local, locoregional, and distant recurrent tumor. Cross-sectional imaging with CT or MRI is recommended for the detailed anatomic delineation of the primary site. PET/CT provides complementary metabolic information and can map systemic involvement. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Correlative translational pharmacodynamics data revised

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Supplement Figure 1: Synergistic cytotoxic effect of pembrolizumab combined with vorinostat in HNSCC tissue slice culture. HNSCC slices (250 ï­m) were cultured and treated with 20 ï­g/ml of isotype control antibody IgG4 or pembrolizumab, with or without vorinostat (20 ï­M, 100 ï­M) for 6 days. Graph shows the percentage of cleaved-caspase-3+ cells. Unpaired student's tests, P-values are as follows: *p < 0.05, **P < 0.01, ***P< 0.001.

Supplementary Figure from First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors

Background Although effective in multiple liquid tumor indications, chimeric antigen receptor (CAR)-T cells have limited efficacy in solid tumor settings. This is the result, in part, of the challenge differentiating tumor associated antigen (TAA) expression in normal and tumor tissue, heterogeneity of TAA expression in the tumor itself, and the lack of effective strategies to simultaneously enhance effector cell trafficking to, persistence within, and resistance to the suppression found within the tumor microenvironment (TME). Here we describe FT825/ONO-8250, a seven-point edited, off-the-shelf CAR-T cell therapy specifically engineered to address and overcome barriers for effective cell therapy in solid tumors. Methods Induced pluripotent stem cells (iPSCs) were engineered to express a novel CAR targeting HER2, interleukin-7 receptor fusion protein (IL7RF), TGFβ-signal redirection receptor (TGFβ-SRR), high-affinity non-cleavable CD16A (hnCD16), and CXCR2 alongside CD38 and T cell receptor, alpha deletion. Engineered iPSCs were differentiated into alpha-beta T (iT) cells, uniformly expressing engineered transgenes without CD38 or T-cell receptor expression, limiting the risk of graft-versus-host disease from allogeneic therapies. Results FT825/ONO-8250 demonstrated potent and specific CAR-based targeting of tumor target lines across HER2 expression levels (3+ to 1+) from multiple solid tumor indications (figure 1A). CAR-dependent efficacy was further enhanced when combined with therapeutic antibodies to trigger antibody-dependent cellular cytotoxicity (ADCC) via hnCD16. Unlike Herceptin-based primary CAR-T cells, FT825/ONO-8250 demonstrated limited cytotoxicity on multiple normal, non-tumorigenic cell lines, underscoring the preference of FT825/ONO-8250 for HER2 expressed by tumor cells (figure 1B). FT825/ONO-8250 resisted TGFβ-mediated suppression, maintaining robust cytolytic efficacy across multiple rounds of tumor challenge and TGFβ exposure, the result of TGFβ-SRR expression. IL7RF enhanced the persistence of FT825/ONO-8250, and CXCR2 expression enabled specific and potent migration to CXCR2 ligands enriched within diverse solid tumor indications. Finally, we observe robust anti-tumor efficacy in vivo in subcutaneous HER2+ xenograft models (figure 1C). Conclusions FT825/ONO-8250, engineered to (i) preferentially target tumor-expressed HER2 and (ii) overcome solid tumor heterogeneity, resist tumor microenvironment suppression, and enhance solid tumor trafficking, is scheduled for IND submission in 2H 2023. Ethics Approval These studies were approved by Fate Therapeutics Institutional Animal Care and Use Committee and were carried out in accordance with the National Institutes of Health's Guide for the Care and Use of Laboratory Animals.

Supplementary Data from ASCEND-7: Efficacy and Safety of Ceritinib Treatment in Patients with ALK-Positive Non–Small Cell Lung Cancer Metastatic to the Brain and/or Leptomeninges

Study Schema Supplemental figure 1 (no revisions, reuploaded)

Table S1. Patient flow by dose group Table S2. PK parameters of utomilumab following multiple dosing Figure S1. Partial response in a patient with anaplastic thyroid carcinoma (utomilumab 3.6 mg/kg + pembrolizumab 2 mg/kg) at cycle 4 versus baseline. Figure S2. Mean concentration-time profile for pembrolizumab

Reliable biomarkers that can be serially monitored to predict treatment response to immune checkpoint inhibitors (ICIs) are still an unmet need. Here, we present a multiplex immunofluorescence (IF) assay that simultaneously detects circulating tumor cells (CTCs) and assesses CTC expression of programmed death ligand-1 (PD-L1) and interferon regulatory factor 1 (IRF-1) as a candidate biomarker related to ICI use. To assess the potential of CTC PD-L1 and IRF-1 expression as candidate biomarkers for patients with advanced epithelial solid tumors receiving ICIs. We tested the IF CTC assay in a pilot study of 28 patients with advanced solid tumors who were starting ICI. Blood for CTC evaluation was obtained prior to starting ICI, after a single cycle of therapy, and at the time of radiographic assessment or treatment discontinuation. At baseline, patients with 0–1 CTCs had longer progression-free survival (PFS) compared to patients with ≥ 2 CTCs (4.3 vs 1.3 months, p = 0.01). The presence of any PD-L1+ CTCs after a single dose of ICI portended shorter PFS compared to patients with no CTCs or PD-L1− CTCs (1.2 vs 4.2 months, p = 0.02); the presence of any PD-L1+ or IRF-1+ CTCs at time of imaging assessment or treatment discontinuation also was associated with shorter PFS (1.9 vs 5.5 months, p < 0.01; 1.6 vs 4.7 months, p = 0.05). CTC PD-L1 and IRF-1 expression did not correlate with tumor tissue PD-L1 or IRF-1 expression. Strong IRF-1 expression in tumor tissue was associated with durable (≥ 1 year) radiographic response (p = 0.02). Based on these results, CTC PD-L1 and IRF-1 expression is of interest in identifying ICI resistance and warrants further study.

AbstractPurpose: Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non–small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges. Patients and Methods: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses. Results: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6–52.0), 30.0% (16.6–46.5), 50.0% (21.1–78.9), and 59.1% (43.2–73.7); whole-body DCR (95% CI): 66.7% (50.5–80.4), 82.5% (67.2–92.7), 66.7% (34.9–90.1), and 70.5% (54.8–83.2); intracranial ORRs (95% CI): 39.3% (21.5–59.4), 27.6% (12.7–47.2), 28.6% (3.7–71.0), and 51.5% (33.5–69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6–41.4) and DCR was 66.7% (95% CI, 41.0–86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood–brain barrier. Conclusions: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease. See related commentary by Murciano-Goroff et al., p. 2477

Thin-film freeze-drying (TFFD) is a rapid freezing and then drying technique used to prepare inhalable dry powders from the liquid form for applications such as drug delivery to the lungs. Herein we report the preparation of aerosolizable dry powders of monoclonal antibodies (mAbs) by TFFD. We first formulated an IgG antibody with lactose/leucine (60:40, w/w) or trehalose/leucine (75:25) and tested their aerosol performance. The IgG 1% (w/w) formulated with lactose/leucine (60:40, w/w) in phosphate buffered saline (PBS) (IgG-1-LL-PBS) and processed by TFFD was found to produce the powder with desirable aerosol properties. We then replaced the IgG with anti-programmed cell death protein (anti-PD-1 mAb), a specific antibody, to prepare a dry powder (anti-PD1-1-LL-PBS), which performed similarly to the IgG-1-LL-PBS powder. The aerosol properties of the anti-PD1-1-LL-PBS dry powder were significantly better when TFFD was used to prepare the powder than when conventional shelf freeze-drying (shelf FD) was used. The TFFD dry powder had a porous structure with nanoaggregates and had a Tg value between 39 and 50 °C. When stored at room temperature, the anti-PD-1 mAb in the TFFD powder was more stable than that of the same formulation stored as a liquid. The addition of polyvinylpyrrolidone K40 in the formulation raised the Tg to 152 °C, which is expected to further increase the storage stability of the mAbs. The PD-1 binding activity of the anti-PD-1 mAbs after TFFD was not different from before TFFD. While protein loss, likely due to protein binding to vials and the thin-film freezing apparatus, was identified, we were able to minimize the loss by increasing the mAb concentration (i.e., from 1% to 13.2%). Micro-flow imaging revealed that the excipients and PBS affected subvisible aggregate formation. More subvisible mAb aggregates were generated when PBS was used, but the mAb content in the dry powders did not significantly affect the total subvisible aggregate count. Powders prepared with mannitol as an excipient showed the least amount of subvisible mAb aggregates. Finally, we showed that anti-TNF-α, another mAb, can also be converted to a dry powder with a similar composition by TFFD. We conclude that TFFD can be applied to produce stable, aerosolizable dry powders of mAbs for pulmonary delivery and that formulations must be optimized to maximize aerosol performance and minimize protein aggregation.

Aim: Assess factors associated with EGFR TKI initiation among patients with metastatic non-small-cell lung cancer (mNSCLC). Patients & methods: Medicare Part D patients diagnosed with non-squamous mNSCLC and starting an EGFR TKI within 1 year of diagnosis were selected from the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Associations between patient characteristics and time from diagnosis to treatment initiation (time to treatment [TTT]) were analyzed. Results: Among the sample (n = 890), the patients who were younger, Black or from rural communities had significantly longer TTT. Patients who did not receive surgery, who were Asian and those with brain metastases had significantly shorter TTT. Conclusion: Patient demographics and clinical characteristics may affect timeliness of EGFR TKI treatment for mNSCLC. Future research should examine potential barriers to treatment. Tweetable abstract #RWE study finds patients with #metastatic non-small-cell #lungcancer who were younger, Black or from rural communities had longer time to treatment initiation with #EGFR TKIs. Time to initiation was shorter for patients with no surgery, who were Asian or with brain metastases. Plain language summary This study aimed to identify factors that may affect the time to initiate treatment with a product in the EGFR TKI class of drugs for patients with metastatic non-small-cell lung cancer (mNSCLC). We used an anonymized database that combines health information on cancer patients (SEER) with insurance claims information for Medicare Part D patients. Our study included 890 patients. We found that patients who were younger, Black, or from rural communities had longer times to starting treatment. Patients who did not receive surgery, who were Asian and those with cancer that had spread to the brain had notably shorter times to starting treatment. Further research should examine potential barriers that may contribute to treatment initiation delay.

Abstract Purpose: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. Patients and Methods: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2–1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non–small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. Results: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1–2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. Conclusions: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.

BACKGROUND:To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. METHODS:Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106). RESULTS:TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=-0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% ҡ=0.573) among patients whose HPV results were available using both methods. CONCLUSIONS:TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed. TRIAL REGISTRATION NUMBER:NCT01848834.

PURPOSE Immunotherapy has revolutionized the treatment of advanced non–small-cell lung cancer (NSCLC). In two phase III trials (CheckMate 017 and CheckMate 057), nivolumab showed an improvement in overall survival (OS) and favorable safety versus docetaxel in patients with previously treated, advanced squamous and nonsquamous NSCLC, respectively. We report 5-year pooled efficacy and safety from these trials. METHODS Patients (N = 854; CheckMate 017/057 pooled) with advanced NSCLC, ECOG PS ≤ 1, and progression during or after first-line platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg once every 2 weeks) or docetaxel (75 mg/m2 once every 3 weeks) until progression or unacceptable toxicity. The primary end point for both trials was OS; secondary end points included progression-free survival (PFS) and safety. Exploratory landmark analyses were investigated. RESULTS After the minimum follow-up of 64.2 and 64.5 months for CheckMate 017 and 057, respectively, 50 nivolumab-treated patients and nine docetaxel-treated patients were alive. Five-year pooled OS rates were 13.4% versus 2.6%, respectively; 5-year PFS rates were 8.0% versus 0%, respectively. Nivolumab-treated patients without disease progression at 2 and 3 years had an 82.0% and 93.0% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression-free at 5 years, respectively. Treatment-related adverse events (TRAEs) were reported in 8 of 31 (25.8%) nivolumab-treated patients between 3–5 years of follow-up, seven of whom experienced new events; one (3.2%) TRAE was grade 3, and there were no grade 4 TRAEs. CONCLUSION At 5 years, nivolumab continued to demonstrate a survival benefit versus docetaxel, exhibiting a five-fold increase in OS rate, with no new safety signals. These data represent the first report of 5-year outcomes from randomized phase III trials of a programmed death-1 inhibitor in previously treated, advanced NSCLC.