Sequential Dosing of Next-Generation IMA203CD8 TCR-T-Cell Therapy Targeting PRAME in Combination with BRAF-/MEK-Inhibition in a Melanoma Patient with Progressive Disease - a Case Report
Authors: Schmitz Friederike , Schumacher Martin , Heine Annkristin , Busch Annette , Heine Mario , Luetkens Julian A. , Landsberg Jennifer , Schäfer Niklas , Ebert Oliver , Zeiser Robert , Gribben John G. , Brossart Peter , Holderried Tobias A.W. 
Published: December 2024

Background:
T-cell-receptor (TCR)- T-cell therapies have shown promising results in cancer patients, most notably to date in patients with advanced melanoma. However, there is little data on delayed sequential dosing of TCR-T-cell therapies in patients with progressive disease. Split-dosing of TCR or CAR (chimeric antigen receptor)-T cells has been performed mostly to decrease toxicity and to increase total cell dose by infusion of the cells on two or three consecutive days. We postulated first that a “second hit” of tumor directed TCR-T cells might increase anti-tumor activity and lead to an altered and improved TCR-T-cell evolution in vivo with reduced T-cell exhaustion and second, that combination therapies of TCR-T cells with BRAF/MEK-inhibition (MAPKi) would be safe and could lead to synergistic activity.
Methods:
In support of these hypotheses we report on a 64-year-old male patient with advanced melanoma and progressive disease. The patient was screened for the IMA203CD8 trial but found to be non-eligible due to high tumor volume. Instead, he received IMA203CD8 as compassionate use with two sequential doses of IMA203CD8 TCR-T-cell therapy targeting PRAME combined with MAPKi at the University Hospital of Bonn, Germany.
Results:
Since his initial diagnosis in 2020, the patient experienced several relapses under treatment (radiotherapy, MAPKi, immune checkpoint inhibition and radiotherapy) and was eventually included in the IMA203CD8 trial. However, rapid progression of the disease made him ineligible from the trial. With no alternative therapeutic options available, he underwent a compassionate use treatment attempt with IMA203CD8. After standard lymphodepletion, the patient received the first dose of IMA203CD8 on day 0 (400 TCR-T cells/m2 BSA ), and the second infusion of IMA203CD8 on day +11 (800 TCR-T cells/m2 BSA). On day +1 after first IMA203CD8 infusion, the patient developed cytokine release syndrome (CRS) grade II with fever and oxygen dependency as well as a CRS-related immune effector cell associated neurotoxicity syndrome (ICANS) grade II. Dexamethasone and Tocilizumab were initiated, which led to quick termination of ICANS but he had continuous high fever and intermittent oxygen dependency (CRS grade II), so that Anakinra was added alongside high-dose Dexamethasone and Tocilizumab on day +3. With this, CRS improved to grade I on day +5 and completely resolved on day +8. The patient developed delirium on day +7 with visual phenomena and thought disorder. A CT-scan of the brain was unremarkable. Under short-course low-dose neuroleptic medication the symptoms rapidly resolved. Interleukin 2 (IL-2) was administered on day +9 and +10 in keeping with the trial protocol. On day +11 the patient received the second IMA203CD8 infusion which resulted only in self-limiting CRS grade I with fever on days +14 and +15 and no ICANS. IL-2 was administered from day +12 until day +21 without incident. The patient was discharged on day +22 with no additional toxicities and in overall good condition. Subsequent outpatient monitoring did not show further events. In the first follow-up on day +42 after the first IMA203CD8 infusion, the patient showed remarkable tumor reduction and is in good condition at the time of submission.
Conclusion:
Here we present for the first time that a delayed sequential application of IMA203CD8 TCR-T cells in a heavily pretreated melanoma patient with progressive disease is safe and well manageable. Clinically, the second infusion also led to a second TCR-T-cell response with low grade CRS, but despite prolonged CRS after the first infusion and the increased second cell dose, this did not lead to severe toxicities. Additionally, as we could previously show with IMA203 TCR-T cells, IMA203CD8 TCR-T cells can be administered simultaneously with MAPKi and the combination is feasible, safe, and possibly beneficial. Although the individual contribution of the second IMA203CD8 infusion on the tumor response currently cannot be ultimately distinguished, longer follow-up and detailed assessment of the immune response will shed more light on the potential benefits of a delayed second infusion of T-cell therapies, as this novel approach could help increase anti-tumor activity of TCR- and CAR-T-cell therapies and enhance T-cell status potentially long-term with reduced T-cell exhaustion.