Intratumoral application of human myeloid dendritic cells: a novel approach to treating refractory advanced melanoma, NSCLC and recurrent glioblastoma

Since the approval of immune checkpoint blockade (ICB) including anti-programmed death protein-1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein-4 (CTLA-4) monoclonal antibodies (mAb) for the treatment of advanced cancer, the treatment landscape has been significantly reshuffled. However, only a minority of patients respond, and most patients will eventually need other treatment options. The use of cancer immunotherapy relies on the fundamental principles of the human immune system, following different steps as describedv in the cancer immunity cycle. In my research, we set out to investigate a multimodal treatment protocol for the treatment of patients who stop responding to ICB (melanoma and non-small cell lung cancer [NSCLC]) or patients with tumor types that traditionally do not respond (glioblastoma) by intervening in different steps along the cycle. It has now extensively been demonstrated that dendritic cells are central players in the antitumor immune response by coordinating both the initial antigen recognition and priming of T cells as well as modulating the immunological tumor microenvironment. Therefore, based on results previously published by our research group, the intratumoral (IT) use of autologous CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells (myDC) was a central component in these multimodal treatments. First, we validated the synergistic effect of combining treatment with the oncolytic virus Talimogene laherparepvec (T-VEC) and myDC in a preclinical seUng. We demonstrated that T-VEC-treated melanoma cells can activate myDC, can be taken up by myDC, and presented to antigen-specific T cells. This confirms a biological basis for the clinical responses observed in the previously published MyDCTV trial (Schwarze, Tijtgat et al. JITC 2022) in which advanced melanoma patients were treated with this combination. Encouraged by these results, we set up a new first-in-human clinical trial. However, due to the unavailability of TVEC in Belgium and its high price, we searched for an alternative. In light of its immunostimulatory properties and reported positive effects on myDC, we investigated a weekly IT administration of the synthetic adjuvant system 01 (AS01) combined with IT and intravenous (IV) ICB with IT myDC administration. The trial demonstrated good feasibility and no severe AE, with encouraging results including durable ongoing responses in 3 out of 8 patients (6 evaluable). Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration in tumors from responding patients, with a reduced mean distance between T-cells and tumor cells.

In the context of NSCLC, patients frequently present with oligoprogression after initial treatment with ICB (alone or in combination therapy) for which stereotactic body radiation therapy (SBRT) is proposed. We investigated in a Phase II randomized clinical trial whether adding IT (including CT-guided) myDC and ICB has an additional effect in these patients. In some patients, promising signs of activity were observed. However, the primary endpoint of 1-year PFS has not been met and recruitment was terminated early.

Patients treated with ICB presenting with intracranial lesions often receive SBRT to the brain. A known side-effect is focal radiation necrosis of the brain (fRNB). In a retrospective case series of 13 patients, we demonstrated that a fixed, low-dose regimen of the anti-VEGF mAb bevacizumab can be an effective and cost-reducing alternative for standard-dose bevacizumab and likely has fewer side effects as compared to long-term high-dose corticosteroid use. Finally,
we also investigated the use of myDC in the context of recurrent glioblastoma as part of a bigger, adaptive clinical trial program involving the use of ICB (both locally administered as well as IV). Three out of 12 patients from the initial cohort treated with myDC survived for more than two years since the start of treatment. This cohort was therefore expanded with six patients, of which 4 remain on treatment and without progression. As an exploratory analysis, we also investigated if patients, across all cohorts of this clinical trial, had an improved PFS after being treated with the VEGF-inhibitor bevacizumab as compared to a historic cohort of patients treated with VEGF inhibitors. We observed that globally all patient cohorts do becer, but especially the myDC-containing cohort outperforms the others.

In conclusion, this thesis demonstrates that a multimodal treatment involving autologous CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myDC for patients that are resistant to ICB can lead to durable disease responses in different tumor types including melanoma, glioblastoma, and NSCLC. Furthermore, using VEGF-blocking therapy can be a corticoid-sparing alternative for the treatment of fRNB as well as cerebral edema in the case of (pseudo)progressive glioblastoma in the context of treatment with ICB.