Feasibility and Safety of Personalized, Multi-Target, Adoptive Cell Therapy (IMA101): First-In-Human Clinical Trial in Patients with Advanced Metastatic Cancer.
Apostolia-Maria TsimberidouKerstin GuentherBorje S AnderssonRegina MendrzykAmir AlpertClaudia WagnerAnna NowakKatrin AslanArun SatelliFabian RichterSabrina Kuttruff-CoquiOliver SchoorJens FritscheZoe CoughlinAli S MohamedKerry SiegerBecky NorrisRita OrtJennifer BeckHenry Hiep VoFranziska HoffgaardManuel RuhLinus BackertIgnacio I WistubaDavid FuhrmannNuhad K IbrahimVan Karlyle MorrisBryan K KeeDaniel M HalperinGraciela Nogueras GonzalezPartow KebriaeiElizabeth J ShpallDavid J ViningPatrick HwuHarpreet Singh-JasujaCarsten ReinhardtCedrik M BrittenNorbert HilfToni WeinschenkDominik MaurerSteffen WalterPublished in: Cancer immunology research (2023)
IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 pre-defined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose interleukin-2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with T-cell products. IMA101 treatment was feasible and well tolerated. The most common adverse events were cytokine release syndrome (Grade 1, n=6; Grade 2, n=4) and expected cytopenias. No patient died during the first 100 days after T-cell therapy. No neurotoxicity was observed. No objective responses were noted. Prolonged disease stabilization was noted in three patients lasting for 13.7, 12.9, and 7.3 months. High frequencies of target-specific T cells (up to 78.7% of CD8+ cells) were detected in the blood of treated patients, persisted for >1 year, and were detectable in post-treatment tumor tissue. Individual TCRs contained in T-cell products exhibited broad variation in TCR avidity, with the majority being of low-avidity. High-avidity TCRs were identified in some patients' products. This study demonstrates the feasibility and tolerability of an actively personalized ACT directed to multiple defined pHLA cancer targets. Results warrant further evaluation of multi-target ACT approaches using potent high-avidity TCRs.
Keyphrases
- cell therapy
- end stage renal disease
- low dose
- newly diagnosed
- chronic kidney disease
- ejection fraction
- clinical trial
- prognostic factors
- small cell lung cancer
- peritoneal dialysis
- acute lymphoblastic leukemia
- stem cells
- type diabetes
- signaling pathway
- cell proliferation
- oxidative stress
- insulin resistance
- adipose tissue
- patient reported outcomes
- immune response
- cell death
- pregnant women
- bone marrow
- polycystic ovary syndrome