BackgroundGEN-009 adjuvanted personalized cancer vaccine contains up to 20 neoantigens selected by ATLAS™, an ex vivo bioassay screening autologous T-cells for immune responses against both ...neoantigens and Inhibigens™. Inhibigen-specific T-cells suppress immunity, have been shown to accelerate tumor progression in mice, and are excluded from GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Ninety-nine percent of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively.1 Six of 8 patients continue without progression with a median follow up >2 years.MethodsGEN-009 was administered to patients with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with single agent anti-PD-1. Patients who progressed prior to vaccination received salvage therapy followed by GEN-009 in combination. Peripheral T-cell responses were measured by ex vivo and in vitro stimulated fluorospot assays. Circulating tumor (ct) DNA levels were evaluated in a subset of patients pre- and post-GEN-009 administration.Results15 patients received GEN-009 in combination with PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (range 5–18). GEN-009-related adverse events were limited to vaccine injection site reactions, mild myalgias or fatigue. Sequential vaccination with GEN-009 had an additive effect on the magnitude of ex vivo T-cell responses, that persisted in some patients for 12+ months post first vaccine dose. An association between proportion of peptides eliciting significant cytokine responses and RECIST response is apparent. Epitope spread was detected in CD8+ T-cells from CPI-sensitive patients, but not refractory patients. Four patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further tumor reduction after GEN-009 vaccination. Seven of 9 CPI responsive patients are progression-free 7 to 18 months after first vaccine dose. Three of 7 CPI-refractory patients have experienced unexpected prolonged stable disease, with 2 PR and 1 SD after vaccination lasting up to 10 months. Plasma ctDNA kinetics mirrored RECIST responses in each tested patient; in some responders, all evidence of ctDNA disappeared, including non-targeted antigens.ConclusionsVaccination with GEN-009 alone or in combination with anti-PD-1 was well tolerated. Preliminary data demonstrate induction of robust, durable neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study.Trial Registration clinicaltrials.gov identifier: NCT03633110ReferencesLam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March;11(3):696–713.Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1
BackgroundNKTR-255 is an investigational IL-15Rα-dependent, polymer-conjugated, recombinant human IL-15 agonist designed to provide sustained pharmacodynamic (PD) responses without the need for daily ...dosing. NKTR-255 engages all IL-15 receptor binding complexes to expand, proliferate and activate natural killer (NK) and CD8+ T-cells. This Phase 1b/2 trial (NCT04616196) evaluates NKTR-255+cetuximab in highly refractory patients with head-and-neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC).MethodsSuccessive cohorts received escalating doses of NKTR-255 (q3w) +cetuximab (250mg/m< sup >2 weekly), 1 week after a loading dose of cetuximab alone. Safety (CTCAEv5.0; MTD/recommended Phase 2 dose RP2D) and efficacy (RECISTv1.1) were measured. PK/PD analyses were conducted, including assessment by flow cytometry/plasma cytokine analysis. Fold-change was calculated as treatment over baseline for NKTR-255 (baseline=1).ResultsAs of August 15, 2021, 12 patients had received ≥1 dose of NKTR-255+cetuximab; (37–70 years; 92% male; HNSCC n=4, CRC n=8; NKTR-255 1.5µg/kg n=7, NKTR-255 3.0µg/kg n=5). Patients had received a median 3.5 lines of prior therapy for metastatic disease. 11 patients had no response to the most recent prior therapy. Of the 12 patients, seven remain on treatment, with five not yet reaching first scan. RP2D has not yet been reached; dose escalation is ongoing.10 patients experienced an AE; one G5 AE occurred (due to progression). Seven patients reported NKTR-255-related AEs (all G1-2, except one G3 which resolved in 24 hours). Any-cause AEs in ≥20% were acneiform dermatitis, fatigue, and infusion-related reaction.Treatment-induced transient changes in inflammatory cytokines, including IFNy, MCP-1 and IL-6, at 1.5µg/kg (n=3) peaked 4 hours post-infusion and resolved by 24-48 hours. Mean T1/2 of NKTR-255 (1.5µg/kg dose, first cycle) was 27.8 hours.Dose-dependent expansion of NK and CD8+ T-cells was observed in peripheral blood. For NK cells, mean peak fold-change was ~4-fold and ~6-fold, and for CD8+ T-cells was ~2-fold and ~3-fold (1.5µg/kg and 3µg/kg dose levels, respectively). NK and CD8+ T-cells demonstrated increased Ki67+ proliferative ability.As of August 15, four patients in the 1.5µg/kg NKTR-255 dose cohort were response-evaluable: one CRC patient (4 prior metastatic treatment lines) reported a confirmed PR (–52%) after 3 cycles; two HNSCC patients reported SD.ConclusionsNKTR-255 was biologically active and led to expansion and proliferation of NK and CD8+ T-cells. Early dose-escalation data suggest that NKTR-255+cetuximab is safe and tolerable with preliminary anti-tumor activity. Updated data will be presented. NKTR-255, alone and in combination with daratumumab and rituximab, is also being evaluated in liquid tumors.AcknowledgementsThe authors thank the patients and their families involved in the trial.Trial RegistrationNCT04616196Ethics ApprovalThe study was approved by site IRBs.ConsentN/A
BackgroundImmuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in ...clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of attenuated human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers.MethodsCUE-101–01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum-based or checkpoint inhibitor therapy and in combination with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs followed by expanded enrollment at the recommended phase 2 dose (RP2D). Therapy was administered every 3 weeks until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed.ResultsAs of June 22, 2023, 71 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both monotherapy and pembrolizumab combination cohorts. Monotherapy RP2D enrollment is complete and combination RP2D enrollment is ongoing. Adverse events have been manageable and are consistent with the CUE-101 mechanism of action and underlying disease. Grade 3 AEs reported include lymphocyte count decreased (11.3%), anemia (7.0%), decreased appetite and infusion-related reaction (4.2%). PD data demonstrate selective expansion of HPV-16 E711–20-specific CD8+ T cells, sustained increase in NK cells with only transient increase in Treg cells. Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 14 months. Among 16 evaluable RP2D CUE-101 and pembrolizumab combination patients at data cut-off, 1 uCR, 4 PRs, 2 uPR, and 4 durable SDs were observed. Of the 7 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 2 patients pending analysis at time of data cut-off.ConclusionsCUE-101 demonstrates safety, tolerability and results in clinical benefit. Patients treated with CUE-101 monotherapy in 3L showed a long OS and CUE-101 and pembrolizumab combination resulted in an ORR of 44% with a corresponding decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and support from LG Chem, Ltd., Seoul, South Korea.Trial RegistrationClinicaltrials.gov NCT03978689Ethics ApprovalThis study was approved by IRBs at all study sites: Advarra Pro00037736, IRB 52744, HRPO# 201905108, DF/HCC IRB# 19–374, WIRB STUDY00008948, IRB 191714, 2019–087, WIRB 2000026098, 2019–0578, WIRB 1908869642, WIRB IRB00112341, IRB 20–073, IRB00255391, IRBMED HUM00165746, US Oncol IRB00001113, WCG IRB00000533.
BackgroundImmuno-STATsTM are novel, modular fusion proteins designed to selectively activate tumor-antigen-specific CD8+ T cells. CUE-101 is comprised of a human leukocyte antigen (HLA) complex, ...HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of a reduced affinity human interleukin-2 (IL-2) and is designed to bind and activate HPV16-specific T cells for treatment of HPV16-driven cancers. In preclinical studies CUE-101 demonstrated selective binding, activation, and expansion of HPV16 E7-specific CD8+ T cells, and a murine surrogate activated anti-tumor immunity.1 MethodsCUE-101-01 is a first-in-human study in HLA-A*0201 positive patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Safety of escalating monotherapy and combination doses was evaluated to establish the recommended phase 2 dose (RP2D) for expanded enrollment. Patients with R/M HNSCC refractory to 1 or more prior platinum or pembrolizumab based systemic treatments received CUE-101 monotherapy, and patients with R/M HNSCC and PD-L1 tumor expression received combination CUE-101 and 200 mg pembrolizumab as first line treatment. Study treatment was administered intravenously every 3 weeks until progression or toxicity. Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.ResultsAs of June 30, 2021, 39 patients have received CUE-101 monotherapy ranging from 0.06 to 8 mg/kg. The maximum tolerated dose (MTD) was not identified. Based on PK, PD and clinical data, a monotherapy RP2D of 4 mg/kg was selected. The combination cohort of 1 mg/kg CUE-101 and pembrolizumab has been tested and dose escalation is ongoing. Adverse events have included CTCAE grade 2 or less fatigue (41%), anemia (31%), lymphopenia (24%), chills (21%), decreased appetite (19%) and dyspnea (17%). CUE-101 PK data demonstrate dose-dependent increases in drug exposure that are sustained upon repeat dosing. PD data demonstrate dose-dependent expansion of HPV-16 E711-20-specific CD8+ T cells, sustained increase in natural killer cells and transient increase in Treg cells. An increase in CD3+ GZMB+ tumor infiltrating T cells was observed in tissue following treatment with CUE-101 in one patient with available pre- and post-treatment biopsies. One patient at the CUE-101 monotherapy RP2D has an ongoing partial response and 8 of 33 patients have experienced stable disease ≥ 12 weeks based on RECIST 1.1 criteria.ConclusionsCUE-101 is a novel immunotherapeutic demonstrating acceptable safety and tolerability with encouraging PD signals, supporting selective activation of tumor-specific T cells, and promising antitumor activity. Enrollment continues in both monotherapy and combination cohorts.AcknowledgementsThe authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma.Trial RegistrationClinicalTrials.gov NCT03978689ReferencesQuayle SN, Girgis N, Thapa DR, et al. CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc fusion protein, enhances tumor antigen specific T cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res 2020;26:1953–64.Ethics ApprovalThis study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center), HRPO# 201905108 (Washington University School of Medicine), 2019–087 Karmanos Cancer Institute, DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB 2000026098 (Yale Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB STUDY00008948 (University of Washington, Seattle), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), 2019–0578 (The University of Texas MD Anderson Cancer Center), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine).
To retrospectively review our institutional experience with hypopharyngeal carcinoma with respect to treatment modality.
A total of 70 patients with hypopharyngeal cancer treated between 1999 and ...2009 were analyzed for functional and survival outcomes. The treatments included surgery alone (n = 5), surgery followed by radiotherapy (RT) (n = 3), surgery followed by chemoradiotherapy (CRT) (n = 13), RT alone (n = 2), CRT alone (n = 22), induction chemotherapy followed by RT (n = 3), and induction chemotherapy followed by CRT (n = 22).
The median follow-up was 18 months. The median overall survival and disease-free survival for all patients was 28.3 and 17.6 months, respectively. The 1- and 2-year local control rate for all patients was 87.1% and 80%. CRT, given either as primary therapy or in the adjuvant setting, improved overall survival and disease-free survival compared with patients not receiving CRT. The median overall survival and disease-free survival for patients treated with CRT was 36.7 and 17.6 months vs. 14.0 and 8.0 months, respectively (p < .01). Of the patients initially treated with an organ-preserving approach, 4 (8.2%) required salvage laryngectomy for local recurrence or persistent disease; 8 (16.3%) and 12 (24.5%) patients were dependent on a percutaneous gastrostomy and tracheostomy tube, respectively. The 2-year laryngoesophageal dysfunction-free survival rate for patients treated with an organ-preserving approach was estimated at 31.7%.
Concurrent CRT improves survival in patients with hypopharyngeal cancer. CRT given with conventional radiation techniques yields poor functional outcomes, and future efforts should be directed at determining the feasibility of pharyngeal-sparing intensity-modulated radiotherapy in patients with hypopharyngeal tumors.
JNJ-64041757 (JNJ-757) is a live, attenuated, double-deleted Listeria monocytogenes–based immunotherapy expressing human mesothelin. JNJ-757 was evaluated in patients with advanced NSCLC as ...monotherapy (phase 1) and in combination with nivolumab (phase 1b/2).
Patients with stage IIIB/IV NSCLC who had received previous therapy were treated with JNJ-757 (1 × 108 or 1 × 109 colony-forming units CFUs) alone (NCT02592967) or JNJ-757 (1 × 109 CFU) plus intravenous nivolumab 240 mg (NCT03371381). Study objectives included the assessment of immunogenicity, safety, and efficacy.
In the monotherapy study, 18 patients (median age 63.5 y; women 61%) were treated with JNJ-757 (1 × 108 or 1 × 109 CFU) with a median duration of 1.4 months (range: 0–29). The most common adverse events (AEs) were pyrexia (72%) and chills (61%), which were usually mild and resolved within 48 hours. Peripheral proinflammatory cytokines and lymphocyte activation were induced posttreatment with transient mesothelin-specific T-cell responses in 10 of 13 biomarker-evaluable patients. With monotherapy, four of 18 response-evaluable patients had stable disease of 16 or more weeks, including one patient with a reduction in target lesions. In the combination study, 12 patients were enrolled (median age 63.5 y; women 33%). The most common AEs with combination therapy were pyrexia (67%) and chills (58%); six patients had grade 3 AEs or greater, including two cases of treatment-related fatal pneumonitis. The best overall response for the combination was stable disease in four of nine response-evaluable patients.
As monotherapy, JNJ-757 was immunogenic and tolerable, with mild infusion-related fever and chills. The limited efficacy of JNJ-757, alone or with nivolumab, did not warrant further investigation of the combination.
Little information is available regarding the imaging characteristics that assist in differentiating responders from non-responders. We hypothesized that patients with higher pretreatment tumor ...volume (PTV) would have lower response rates and shorter overall survival (OS).
Data from patients who received at least one dose of program death-1 (PD-1) inhibitors before August 31, 2016 were captured from our institution's pharmacy database. The primary objective was to determine the association of PTV with best response, evaluated utilizing RECIST v1.1 criteria. Secondary objectives were estimation of progression-free survival (PFS) and OS. PTV was measured using the Philips Intellispace Multi-Modality Tumor Tracking application.
116 non-small cell lung cancer (NSCLC) patients were evaluated. 66% patients had adenocarcinoma, 28% had squamous cell carcinoma and 5% had poorly differentiated NSCLC. Median PTV was 53.7 cm
(95% CI: 13.3-107.9). Only one individual had no metastases and the remainder had M1 disease; 38% M1a, 10% M1b, 51% M1c. Most (79%) were previously treated. There were no complete responses; among those followed for at least 6 weeks, 26% had a partial response, 39% stable disease and 34% PD; 4% had no recorded response. There were no strong associations of PTV with any of the demographic or clinical characteristics. There was no association between PTV and OS (HR 1.2,
=0.26) or PFS (HR 1.1,
=0.47). Liver metastasis was associated with shorter survival (HR=2.8,
=0.05).
PTV in NSCLC did not prove to be a predictor of response to PD-1 inhibitors but having liver metastasis was associated with significantly shorter survival.
BackgroundGEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS™, an ex vivo bioassay screening autologous T cells to identify both neoantigens as ...well as Inhibigens™ empirically and without in silico predictions. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice. Inhibigens are avoided in GEN-009. Previous data from patients treated with GEN-009 monotherapy showed 99% of selected peptides generated immune responses including ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides respectively.MethodsGEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing; they subsequently received 5 vaccine doses over 24 weeks in combination with the PD-1 inhibitor. Patients who progressed prior to vaccination could receive alternate therapy followed by GEN-009 combined with an appropriate salvage regimen. Peripheral T cell responses were evaluated pre-and post-vaccination by dual-analyte fluorospot assays measured both directly ex vivo and after in vitro stimulation.ResultsAs of August 18, 2020, 15 pts received GEN-009 in combination with a PD-1 inhibitor. Their median TMB was 1.37Mut/mb (range 0.31–6.55), with a median of 24 (6–99) neoantigens and 16 (1–86) Inhibigens. The number of neoantigens in each manufactured vaccine ranged from 4–18 (median 13). GEN-009-related adverse events were limited to Grade 1 injection site reactions. Ex vivo T cell responses peaked after the third vaccination for IFNγ and some patients showed evidence of epitope spread. The initial 5 patients are evaluable for antitumor activity with at least 3 months follow up after first vaccination. Three patients experienced early tumor responses followed by stabilization on PD-1 inhibitor SOC and demonstrated a further reduction in tumor volume after GEN-009 vaccination (figure 1). One patient experienced a complete response prior to vaccination and the 5th patient had progression on SOC, but had a Partial Response to salvage and remains stable after vaccination.Abstract 390 Figure 1Individual patient spider plots. Percent change in target lesion diameter over timeConclusionsVaccination with GEN-009 in combination with PD-1 CPI is feasible for patients with advanced solid tumors with little additive toxicity. Preliminary data demonstrate induction of robust, neoantigen-specific immune responses and a potential expansion of stimulatory targets with epitope spreading in the presence of PD-1 inhibitor. Possible additive antitumor activity in combination with PD-1 inhibitors is suggested by tumor shrinkage following GEN-009 dosing. More mature response and immunogenicity data on 10 additional patients is anticipated for November.Trial RegistrationClinicalTrials. gov NCT03633110Ethics ApprovalThe study was approved by Western Institutional Review Board, approval number 1-1078861-1.
•Adoptive cell therapy includes tumor-infiltrating lymphocytes and engineered T cells.•Targets antigens are self-proteins, cancer testes antigens or tumor-specific antigens.•CD19-targeted CAR T cells ...have shown promising results in B-cell malignancies.•On-target toxicity is caused by targeting tumor antigens shared by normal tissues.•Cytokine release syndrome and neurotoxicity are potential adverse effects of CAR T.
Adoptive cellular therapy (ACT) is an immunotherapy which involves the passive transfer of lymphocytes into a lymphodepleted host after ex vivo stimulation and expansion. Tumor-infiltrating lymphocytes (TILs) have shown objective tumor responses mainly restricted to melanoma and rely on a laborious manufacturing process. These limitations led to emergence of engineered cells, where normal peripheral blood lymphocytes are modified to express T cell receptors (TCRs) or chimeric antigen receptors (CARs) specific for tumor-associated antigens (TAAs). To date, CD19-targeted chimeric antigen receptor T (CAR T) cells have been the most extensively studied, showing complete and durable responses in B-cell malignancies. Antitumor responses with engineered T cells have often been accompanied by undesired toxicities in clinical trials including cytokine release syndrome (CRS) and neurotoxicity. In this review, we provide an overview of adoptive cellular strategies, early and ongoing clinical trials, adverse events and strategies to mitigate side effects and overcome limitations.
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