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Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

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.

Supplementary material

Purpose:Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp.Patients and Methods:Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment.Results:Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway–related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival.Conclusions:These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.

Afami-cel is a mixed CD4+ CD8+ autologous T-cell therapy engineered to target the cancer testis antigen melanoma-associated antigen A4 in HLA-A*02-positive patients with advanced/metastatic synovial sarcoma or myxoid/round cell liposarcoma (MRCLS). Pooled data from the Phase 1 (NCT03132922) and Phase 2 (SPEARHEAD-1, NCT04044768) trials of afami-cel showed an acceptable benefit to risk profile with an overall response rate of 36.2% and a median duration of response of 52.0 weeks.1 To support the continued investigation of potential mechanisms of durable anti-tumor activity, we previously showed that afami-cel induces broad and enduring peripheral cytokine responses2 and that afami-cel tumoral infiltration is associated with increased presence of activated and proliferative cytotoxic T-cells in the tumor microenvironment.3 Here, we report the results of translational analyses exploring the cooperation between afami-cel-induced innate and adaptive immune responses pooled from the Phase 1 and 2 trials. Methods included measurement of 92 biomarkers related to apoptosis, chemotaxis, metabolism, tumor immunity promotion/suppression, and vascular/tissue remodeling in pre- and post-infusion serum samples from 38 patients. We also conducted multiplex immunofluorescence and gene set variation analysis of Reactome immune system pathway categories and microenvironment cell populations in RNA sequencing data from pre- and post-infusion biopsies from ≥15 patients. Serum analyses showed that patients with a clinical benefit as defined by RECIST v1.1 had significantly greater post-infusion levels of chemotactic markers (Kruskal-Wallis; p Citation Format: Cheryl McAlpine, Martin Isabelle, Robyn Broad, Revashnee Naidoo, Ashley Liddle, Elizabeth Duperret, Paul Noto, Ruoxi Wang, Dzmitry Batrakou, Sumit Middha, Chris Evans. Afamitresgene autoleucel (afami-cel; formerly ADP-A2M4) demonstrates durable clinical responses by inducing broad immune engagement with anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 892.

Purpose: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. Patients and Methods: Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment. Results: Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway–related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival. Conclusions: These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.

BackgroundAutologous cell therapies with an engineered T-cell receptor targeting MAGE-A4 have shown responses in patients with synovial sarcoma1 with additional responses in myxoid/round cell liposarcoma (MRCLS), head and neck, lung, esophagogastric junction, and melanoma cancers.2 3 Low-dose radiation may control tumor growth locally and modulate stroma of solid tumors,4 potentially facilitating T-cell infiltration into tumors and antitumor activity.MethodsSub-study designed to assess safety, tolerability, and efficacy in up to 10 patients with low-dose radiation in combination with lymphodepleting chemotherapy, followed by afami-cel (an autologous TCR cell T-cell therapy targeting MAGE-A4). Eligible patients are HLA-A*02^+ with MAGE-A4 expressing tumors including urothelial, melanoma, head and neck, ovarian, non-small cell lung, esophageal, gastric, synovial sarcoma, and MRCLS cancers. Patients receive afami-cel by infusion following low-dose radiation and lymphodepleting chemotherapy. Radiation was 4.2–7 Gy per lesion or isocenter (maximum of 5). Lymphodepleting regimen was IV fludarabine 30 mg/m^2/day for 4 days (−7 to −4) and cyclophosphamide 600 mg/m^2/day for 3 days (−7 to −5). Afami-cel doses ranged from 1.2 x 10^9 to 10 x 10^9 transduced cells. Pts receive afami-cel infusion on Day 1.ResultsAs of Dec 27, 2020, a total of 8 patients, including 4 patients (1 male) with melanoma (2), HNSCC (1), or ovarian (1) cancers received low-dose radiation and afami-cel. Most frequently reported AEs (4/4 pts) were leukopenia/decreased white blood cell count, lymphopenia/decreased lymphocyte count, and neutropenia/decreased neutrophil count; all of which were related to the lymphodepletion regimen. The most commonly (>1 patient) reported AEs considered related to T-cell infusion were cytokine release syndrome (2/4 pts) and fatigue (2/4 pts). Two patients had a total of 5 SAEs: adrenal insufficiency, hyperglycemia, neurotoxicity, pneumonia aspiration, and pneumothorax. The only SAE considered to be related to treatment was Grade 3 neurotoxicity. Best overall responses per RECIST 1.1: 1 partial response (melanoma, −42% in target lesions), 2 stable diseases (ovarian cancer, −23%; HNSCC, no change), and 1 patient did not have post-baseline scans yet. Translational analyses showed peripheral persistence and serum cytokine response profiles consistent with that of afami-cel monotherapy, whilst a relatively greater T cell infiltration in tumor biopsies was evident.ConclusionsAfami-cel with low-dose radiation has had an acceptable safety profile. Most AEs were consistent with those typically experienced by cancer patients undergoing lymphodepletion cytotoxic chemotherapy and cellular therapy. Infused T-cells were observed in tumor biopsies at high frequency, and one patient exhibited a clinical partial response.Trial RegistrationNCT03132922ReferencesVan Tine BA, et al. CTOS 2020.Hong DS, et al. ASCO 2020.Hong DS, et al. SITC 2020.De Selm C, et al. Mol Ther 2018;26(11):2542–2552.

Introduction: Melanoma-associated antigen A4 (MAGE-A4) is a cancer testis antigen expressed in multiple solid tumors. Afami-cel is an autologous, specific peptide enhanced affinity receptor T-cell therapy targeting MAGE-A4 in HLA-A*02+ patients, which has shown promising efficacy in heavily pretreated metastatic synovial sarcoma (SS) and myxoid liposarcoma (MLPS) with cellular features (myxoid/round cell liposarcoma, MRCLS). Assessing MAGE-A4 expression across a wider range of adult and pediatric sarcoma subtypes could identify new therapeutic indications for afami-cel. Methods: Formalin-fixed, paraffin-embedded tissue microarrays from resections of primary and metastatic sarcomas were collected from 1981 to 2015 at The University of Texas MD Anderson Cancer Center. Included sarcomas were: SS (n=70), osteosarcomas (OS; n=107), Ewing sarcomas (ES; n=125), angiosarcoma (n=101), non-uterine leiomyosarcoma (n=186), malignant peripheral nerve sheath tumor (MPNST; n=95), pleomorphic liposarcoma (n=42), MLPS (n=78), uterine leiomyosarcoma (ULMS; n=216), and undifferentiated pleomorphic sarcoma (n=82). Tumors from patients ≤21 years were considered pediatric sarcomas. MAGE-A4 expression intensity (0 to 3+) was assessed by a research-only, non-clinical-trial use, immunohistochemistry assay developed at MD Anderson using a monoclonal antibody (Origene, Rockville, MD). The staining was reported as H-score (range 0–300; [(% positive cells intensity 1) x 1] + [(% positive cells intensity 2+) x 2] + [(% positive cells intensity 3+) x 3]) and percentage of MAGE-A4 expression ≥1+ or 2+. Samples with 30% of tumor cells showing ≥2+ MAGE-A4 expression were considered positive. Results: We analyzed 1102 samples from 702 sarcoma patients. The mean (range) H-score was 26.2 (0–101.9), and 532 (59%) samples were from female patients. Patients’ ages ranged from 5 to 90 years; 124 (11.3%) samples were pediatric. Most common SS was monophasic histology (72%), and most MLPS lacked a cellular component (65%). SS had the highest percentage of MAGE-A4 positivity (47.1%, mean H-score: 101.9), followed by MLPS (16.7%, mean H-score: 36.6), pleomorphic liposarcoma (11.9%), angiosarcoma (9.9%), ULMS (7.4%), MPNST (6.3%), OS (6.5%), LMS (2.7%), and UPS (2.4%). All Ewing sarcoma samples were negative. In pediatric patients, MAGE-A4 positivity was seen only in SS, OS, and angiosarcoma (MAGE-A4 positive rate: 33.3% [5/15], 7.9% [5/62], 25% [1/4], respectively). In MLPS, MRCLS showed significantly more MAGE-A4 positive cases than uniformly myxoid tumors (30% vs 11.8%, Tukey's test, a=0.05). In ULMS, recurrent tumors had significantly more MAGE-A4 positive cases than metastatic tumors (12.1% vs 2.4%, Tukey's test, a=0.05). Conclusions: MAGE-A4 was heterogeneously expressed across 10 sarcoma subtypes. The rates of MAGE-A4 positivity were the highest in SS and MLPS and were lower in other sarcoma subtypes. MAGE-A4 testing in sarcoma subtypes other than SS and MLPS warrants evaluating afami-cel in these ultrarare subtypes of soft tissue sarcomas where treatment options are very limited. Citation Format: Swethajit Biswas, Caddie Laberiano, Khalida Wani, Davis Ingram, Wei Lu, Rossana Lazcano, Wei-Lien Wang, Yao Chen, Dennis Williams, Cheryl McAlpine, Alexander J. Lazar, Luisa M. Solis Soto. Identifying new therapeutic indications for afamitresgene autoleucel (“afami-cel” [formerly ADP-A2M4]) in adult and pediatric sarcomas using MAGE-A4 immunohistochemistry [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A023.

Autologous T-cells engineered with T-cell receptors (TCRs) targeting tumor antigens are promising therapies for metastatic solid cancers.1 Specific peptide enhanced affinity receptor (SPEAR) T-cell therapies are T-cells with engineered HLA-restricted TCRs that precisely target tumor cells with specific antigens, such as MAGE-A4 (a cancer testis antigen), presented on the surface by HLA molecules. In SPEAR T-cell clinical trials targeting MAGE-A4, a 2-step prescreen is done before enrolment. 1) Patients undergo HLA typing via a high-resolution (allelic, 4-digit) sequence-based assay, and those who are positive for the inclusion alleles (HLA-A*02:01P, 02:02P, 02:03P, 02:06P) and not positive for the exclusion allele A*02:05P are eligible. 2) Tumor MAGE-A4 testing is done via an immunohistochemical clinical trial assay (MAGE-A4+ cutoff: ≥30% tumor cell staining at ≥2+ intensity) in HLA-eligible patients. A screening protocol (NCT02636855) has been used in Phase 1 trials of first- and next-generation SPEAR T-cells targeting MAGE-A4 (NCT03132922, NCT04044859) with responses in multiple MAGE-A4+ tumors. As of November 19, 2021, 6,168 patients with 9 solid tumor types were screened at 32 sites across North America and Europe in this screening protocol; among which, 2,744 were HLA-eligible (eligibility rate: 45%, range per tumor type: 42%-55%). HLA-A*02:01 was the most frequent HLA-A*02 allele. Of these HLA-eligible patients, 1,549 had tumor tissues evaluable for MAGE-A4 expression; among which, 313 were MAGE-A4+ (MAGE-A4+ rate: 20%, range: 8%-54%) (Table). MAGE-A4 showed highest prevalence in synovial sarcoma and myxoid/round cell liposarcoma but was seen across all tumor types investigated. Our results will be discussed in the context of tumor histopathology, disease status, and demography. HLA and MAGE-A4 biomarker data will inform the therapeutic opportunities for SPEAR T-cells targeting MAGE-A4 in metastatic solid cancers. 1. D’Angelo et al. Cancer Discov. 2018;8:944. HLA eligibility and MAGE-A4 prevalence in a screening protocol (NCT02636855) Indication Esophageal cancer Esophagogastric junction cancer Gastric cancer Head and neck squamous cell carcinoma Non-small cell lung cancer Melanoma Ovarian cancer Urothelial cancer Synovial sarcoma and myxoid/round cell liposarcoma HLA screened (N) 284 228 271 601 3189 668 539 270 118 HLA eligible (%) 46 45 43 42 43 50 49 43 55 MAGE-A4 evaluable (N) 104 91 73 200 457 245 225 93 61 MAGE-A4 positive (%) 22 25 8 22 14 16 24 32 54 Citation Format: Tianjiao Wang, Jean-Marc Navenot, Stavros Rafail, Mark Carroll, Ruoxi Wang, Cheryl McAlpine, Swethajit Biswas, Francine Brophy, Erica Elefant, Paige Bayer, Sandra McGuigan, Dennis Williams, George Blumenschein, Marcus Butler, Jeffrey M. Clarke, Justin F. Gainor, Ramaswamy Govindan, Victor Moreno, Janet Tu, David S. Hong. Identifying MAGE-A4-positive tumors for SPEAR T-cell therapies in HLA-A*02-eligible patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB001.

Introduction: Bispecific T cell engagers hold promise for effective cancer treatment. The anti-tumor activity of these therapeutics molecules predominantly relies on their capacity to induce direct killing of tumor cells by engaging the cytotoxic machinery of polyclonal CD8+ T cells. However, the impact of additional functionally different T cell populations that can be engaged alongside CD8+ T cells remains unclear. ImmTAC molecules are a novel class of bispecific fusion proteins that use an affinity-enhanced monoclonal TCR to target tumor antigen-derived peptides presented by HLA, and an anti-CD3 monomeric antibody to engage T cells. Tebentafusp, our lead clinical candidate, targets a gp100-derived peptide and is under clinical investigation in metastatic melanoma. Preliminary data revealed T cell activation, trafficking and infiltration into the tumor bed in patients responding to treatment. Importantly not only CD8+ T cells, but also different subsets of CD4+ T cells appeared to be activated, mobilized and redirected to the tumor site following tebentafusp treatment, suggesting a potential contribution of these T cell subsets to the anti-tumor response. The aim of this study was to investigate in vitro the functional capacity of different T cell populations, besides CD8+ T cells, following ImmTAC-mediated redirection toward cancer cells. Methods: Th1, Th2, Th17 CD4+ T cells, γδ T cells and Mucosal-Associated Invariant T cells (MAIT) were isolated from healthy volunteers and their functional response following exposure to ImmTAC in the presence of target cells was analysed. Results: In addition to CD8+ T cells, other T cell populations, were activated in vitro by ImmTAC and elicited a range of effector functions that may differentially contribute to anti-tumor responses. For example, we found that γδ T cells were able to mount rapid and potent cytokine and cytotoxic responses against cancer cells upon redirection with ImmTAC. The mechanisms that underpin our in vitro observations and the potential correlations in patients treated with tebentafusp are under investigation. Conclusions: Multiple T cells populations display functionally distinct responses following ImmTAC-mediated redirection. These results will add valuable insight to our understanding of bispecific T cell engager mechanism of action. In addition, they will help guide rationale for improving the design of these therapeutic molecules and select appropriate combination strategies. Citation Format: Adel Benlahrech, David K. Cole, Christopher J. Holland, Rupert Kenefeck, Rahul C. Khanolkar, Cheryl McAlpine, Sion Lewis, Angela Valerio-Fernandes, Mariantonella Vardeu, David Berman, Marco Lepore. Functionally distinct T cell subsets contribute to ImmTAC-mediated anti-tumor response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4554.

9523 Background: ImmTAC molecules are unique TCR–anti-CD3 bispecifics that redirect T cells against intracellular antigens. IMCgp100, an ImmTAC targeting melanocyte-expressed gp100 antigen, has demonstrated monotherapy activity in advanced melanoma and can cause rash and cytokine-mediated AEs, hypothesized to be on-target (gp100) or effector (CD3) mediated. A preclinical MoA for T cell bispecifics suggests chemokine CXCL10 redirection of CXCR3+ T cells from blood into antigen-positive tissues; this has not been clinically validated. Methods: 84 HLA-A2+ pts with advanced melanoma (n = 61 cutaneous [CM], n = 19 uveal [UM], n = 4 other) received IMCgp100 (NCT01211262). Serum (n = 40) and PBMC (n = 22) samples were taken pre- and post-infusion to analyze changes in cytokines and circulating T cells. Pre- (n = 16) and post-treatment (n = 11) tumor biopsies were analyzed by IHC for CD3, PD-L1 and gp100 expression; tumor RNA (n = 12) was analyzed for gene expression. Results: IMCgp100 induced a transient increase in IFNg-inducible cytokines, most prominently CXCL10. A greater increase in serum CXCL10 was associated with longer OS (p = 0.0002), tumor shrinkage (p = 0.003), and greater transient reduction in peripheral CXCR3+CD8+ T cells (p = 0.001). Reduction in CXCR3+ CD8+ T cells also trended with longer OS (p = 0.02), and tumor shrinkage (p = 0.03). 3/16 pre-treatment biopsies had < 1% gp100 expression (all progressive disease). 8/11 biopsies post-IMCgp100 had increased CD3+ T cells compared with matched pre-treatment samples (associated with baseline gp100 but not PD-L1 expression). Based on tumor biopsy gene expression analysis, IMCgp100 increased T cell markers, IFNg-inducible and cytotoxicity-related genes. Conclusions: The association of clinical benefit with increased serum CXCL10 and decreased peripheral CXCR3+ T cells supports the MoA of IMCgp100-induced T cell redirection and activation. Tumor biopsy results support IMCgp100 redirection of T cells to antigen-positive tumor. A Phase II trial in CM (NCT02535078), a Phase I/II trial in UM (NCT02570308), and a Pivotal RCT in UM (NCT03070392) are ongoing. Clinical trial information: NCT01211262.

IMCgp100, a first in class immunotherapy, is a T cell redirecting bispecific biologic comprising an affinity enhanced T-cell receptor specific for gp100 and an anti-CD3 scFV. Phase I/IIa data has provided evidence of a favourable safety profile, and durable responses in both cutaneous and uveal melanoma have been observed. To complement the clinical studies we have developed a comprehensive biomarker strategy to aid our understanding of pharmacodynamics, patient response and potential mechanisms of resistance which includes analysis of markers in both the tumour and periphery. The data obtained to date provide evidence of the pharmacodynamic effects of the molecule including chemokine/cytokine release, in both the tumor and periphery, and lymphocyte infiltration into tumors. In addition, changes in the levels of certain chemokines following the first dose of IMCgp100 were associated with tumor shrinkage. The biomarker strategy we have developed forms the basis for the support of the on-going Ph II development of IMCgp100 in both cutaneous and uveal melanoma and for other ImmTAC molecules, as single agents and in combination, for the treatment of solid tumours. Citation Format: Cheryl McAlpine, David Krige, Sandra Herrero-Gonzalez, Sarah Franklin, Jacob Hurst, William Shingler, Sanjay Patel, Andy Johnson, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen. Biomarker strategy to guide the clinical development of ImmTACTM molecules, a novel class of bispecific T cell engaging biologic drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3655. doi:10.1158/1538-7445.AM2017-3655

9531 Background: IMCgp100 is a bispecific biologic capable of redirecting T cells against the melanocyte-associated antigen gp100. In the first-in-human (FIH) clinical trial, preliminary efficacy of IMCgp100 in advanced uveal melanoma (UM) was observed; however, cases of severe T cell-mediated toxicities with the first 2 doses limited dosing to 50 mcg QW. This phase 1 study was designed to implement intra-patient escalation to mitigate toxicity and maximize exposure of IMCgp100. Methods: Using a 3+3 design, HLA-A2+ pts with metastatic UM were treated with low weekly (QW) dosing of IMCgp100 iv at Cycle 1, Day 1 (C1D1) (20 mcg) and C1D8 (30 mcg), followed by the escalated cohort dose administered at C1D15 and beyond. Results: Nineteen metastatic UM pts with a median of 3 prior lines of therapy (range 0 - 8) were treated across 4 target dose cohorts (60, 70, 80, and 75 mcg). Fifteen of 19 pts remain on treatment at the data cutoff (25Nov16). Enrollment completed 15Sep16. DLT was observed in 1 of 6 pts in the 70-mcg cohort (LFT elevation), and 2 of 4 pts treated at 80 mcg QW (LFT and bilirubin elevation). The 80 mcg dose level was not tolerated and a 75 mcg cohort was enrolled. Six pts were treated at 75 mcg without DLT; this dose was identified as the MTD and RP2D. All 3 DLT resolved without corticosteroids and all pts resumed IMCgp100. Frequent related AE included pruritus (84%), pyrexia (84%), fatigue (74%), hypotension (74%) and peripheral edema (63%). Gr 3/4 drug-related AE include AST increased (15%), erythema (15%) and hypotension (15%). Preliminary efficacy data (RECIST v1.1) from 17 evaluable pts (2 pts had insufficient follow-up) showed no objective responses; 12 pts had a BOR of SD (63%) including 4 pts (24%) with a ≥10% reduction in target lesions. With median follow-up of 1.8 mo, the disease control rate (16 wks) was 32%. Conclusions: The intra-patient escalation regimen of IMCgp100 results in a 50% increase in dose above the FIH Phase 1, acceptable safety profile, and preliminary efficacy in UM pts. Considering the dismal prognosis of metastatic UM, the PFS observed in this study is encouraging. A Phase 2 expansion cohort and separate pivotal trial of IMCgp100 in advanced UM are ongoing. Clinical trial information: NCT02570308.

IMCgp100, a first in class immunotherapy, is a T cell redirecting bispecific biologic comprising an affinity enhanced T-cell receptor specific for gp100 and an anti-CD3 scFV. Phase I/IIa data supported a favourable safety profile and durable responses in cutaneous and uveal melanoma (CM and UM) were observed. To complement the clinical studies we have developed a comprehensive biomarker strategy, which includes analysis of markers in both the tumour and periphery, to aid our understanding of pharmacodynamics, patient response and potential mechanisms of resistance. The data obtained provide evidence of the pharmacodynamic effects of chemokine/cytokine release, in both the tumor and periphery, and lymphocyte infiltration into tumors over 2 days post dose. Changes in the levels of certain chemokines following the first dose of IMCgp100 were associated with tumor shrinkage. In addition, biological differences in marker responses were also seen between CM and UM patients. The biomarker strategy developed forms the basis for the on-going Ph II development of IMCgp100 in CM and UM and for other ImmTAC molecules, both as single agents and in combination, for the treatment of solid tumours. Citation Format: Cheryl McAlpine, Sandra Herrero Gonzalez, Lindsay Bawden, David Krige, William Shingler, Andy Johnson, Sanjay Patel, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen. Biomarker Strategy To Guide Clinical Development Of ImmTAC™ molecules , A Novel Class Of Bispecific T Cell Engaging Biologic Drugs. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A35.

3016Background: T cell-based bispecific agents have shown activity in hematologic cancers, but solid tumor efficacy remains elusive. IMCgp100 is a bispecific biologic comprising an affinityenhanced...

Systematic review of clinical measurement.To find and synthesize evidence on the psychometric properties and usefulness of the neck disability index (NDI).The NDI is the most commonly used outcome measure for neck pain, and a synthesis of knowledge should provide a deeper understanding of its use and limitations.Using a standard search strategy (1966 to September 2008) and 4 databases (Medline, CINAHL, Embase, and PsychInfo), a structured search was conducted and supplemented by web and hand searching. In total, 37 published primary studies, 3 reviews, and 1 in-press paper were analyzed. Pairs of raters conducted data extraction and critical appraisal using structured tools. Ranking of quality and descriptive synthesis were performed.Horizon estimation suggested the potential for 1 missed paper. The agreement between raters on quality assessments was high(kappa = 0.82). Half of the studies reached a quality level greater than 70%. Failures to report clear psychometric objectives/hypotheses or to rationalize the sample size were the most common design flaws. Studies often focused on less clinically applicable properties, like construct validity or group reliability, than transferable data, like known group differences or absolute reliability (standard error of measurement [SEM] or minimum detectable change [MDC]). Most studies suggest that the NDI has acceptable reliability, although intraclass correlation coefficients (ICCs) range from 0.50 to 0.98. Longer test intervals and the definition of stable can influence reliability estimates. A number of high-quality published (Korean, Dutch, Spanish, French, Brazilian Portuguese) and commercially supported translations are available. The NDI is considered a 1-dimensional measure that can be interpreted as an interval scale. Some studies question these assumptions. The MDC is around 5/50 for uncomplicated neck pain and up to 10/50 for cervical radiculopathy. The reported clinically important difference (CID) is inconsistent across different studies ranging from 5/50 to 19/50. The NDI is strongly correlated (0.70) to a number of similar indices and moderately related to both physical and mental aspects of general health.The NDI has sufficient support and usefulness to retain its current status as the most commonly used self-report measure for neck pain. More studies of CID in different clinical populations and the relationship to subjective/work/function categories are required.

The concept of G-protein-coupled receptor (GPCR) oligomerization has existed for many years, but has only recently received scrutiny from the pharmaceutical industry. The new interest in this theory has arisen not only because technologies to exploit GPCR oligomers are now available, but also because GPCR oligomerization has the potential to explain previously anomalous pharmacology and to provide an array of new therapeutic targets. The emergence of higher order GPCR organization adds a layer of complexity in the context of cellular control, and indeed drug discovery. This review outlines the current knowledge surrounding the oligomerization of GPCRs and describes effective assays for exploiting oligomerization in drug discovery. The clinical significance of oligomerization and the most promising strategies for therapeutically targeting GPCR oligomers are discussed.