Ilixadencel, a Cell-based Immune Primer, plus Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma: A Randomized Phase 2 Study

Lindskog, Magnus; Laurell, Anna; Kjellman, Anders; Melichar, Bohuslav; Rey, Pablo Maroto; Zieliński, Henryk; Villacampa, Felipe; Bigot, Pierre; Bajory, Zoltán; Parikh, Omi; D, Alba; Jellvert, Åsa; Flaskó, Tibor; Gallardo, Enrique; Caparrós, María José Ribal; Purkalne, Gunta; Suenaert, Peter; Karlsson‐Parra, Alex; Ljungberg, Börje

doi:10.1016/j.euros.2022.03.012

Cited by 6 publications

(2 citation statements)

References 24 publications

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“…This approach effectively modifies the immunosuppressive tumor microenvironment (TME) and successfully activates specific antitumor T cells ( 1 , 2 ). The effectiveness of this concept has been extensively examined through numerous clinical studies, focusing on patients with hepatocellular carcinoma ( 3 ) gastrointestinal stromal tumors (GIST) ( 4 ) and renal cell carcinoma ( 4 – 6 ), with the drug candidate ilixadencel being specifically investigated. In addition, our recent work showed that intratumorally administration of AlloDCs can provoke a strong anti-tumor response when combined with systemic αCTLA-4 treatment in an αCTLA-4 monotherapy resistant model by unleashing a T-cell-dependent response ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment

Ali,

Gao,

Iskantar

et al. 2023

Front. Immunol.

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As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic α4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNγ+ CD8+ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (TRM) CD8+ T cells (CD103+CD49a+CD69+). The combination treatment also led to increased infiltration of CD39+CD103+ tumor-specific CD8+ T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.

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Section: Introductionmentioning

confidence: 99%

Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment

Ali,

Gao,

Iskantar

et al. 2023

Front. Immunol.

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“…The safety and efficacy of ilixadencel in patients with progressing advanced/metastatic gastrointestinal stromal tumors despite ongoing treatment with second or later lines of TKIs were assessed in a phase I clinical trial; intratumoral ilixadencel treatment had an acceptable safety profile and tumor responses were detected in 33% of treated patients [116]. To evaluate the clinical effects of intratumoral ilixadencel on mRCC in combination with nephrectomy and sunitinib, compared with nephrectomy and sunitinib monotherapy, a randomized phase 2 study was conducted; the results found that the study failed to meet its primary endpoints, but the ilixadencel and sunitinib combined treatment was correlated with a numerically higher, nonsignificant, confirmed response rate, including complete responses as compared with sunitinib treatment alone [117]. To re-boost antitumor T-cell immunity in tumors, adding intratumoral allogeneic dendritic cells as an immune-priming step, with anti-CTLA-4 Abs, could improve efficacy.…”

Section: Cellsmentioning

confidence: 99%

Immunotherapeutic Agents for Intratumoral Immunotherapy

Shyr,

Liu,

Chien

et al. 2023

Vaccines

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Immunotherapy using systemic immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cells has revolutionized cancer treatment, but it only benefits a subset of patients. Systemic immunotherapies cause severe autoimmune toxicities and cytokine storms. Immune-related adverse events (irAEs) plus the immunosuppressive tumor microenvironment (TME) have been linked to the inefficacy of systemic immunotherapy. Intratumoral immunotherapy that increases immunotherapeutic agent bioavailability inside tumors could enhance the efficacy of immunotherapies and reduce systemic toxicities. In preclinical and clinical studies, intratumoral administration of immunostimulatory agents from small molecules to xenogeneic cells has demonstrated antitumor effects not only on the injected tumors but also against noninjected lesions. Herein, we review and discuss the results of these approaches in preclinical models and clinical trials to build the landscape of intratumoral immunotherapeutic agents and we describe how they stimulate the body’s immune system to trigger antitumor immunity as well as the challenges in clinical practice. Systemic and intratumoral combination immunotherapy would make the best use of the body’s immune system to treat cancers. Combining precision medicine and immunotherapy in cancer treatment would treat both the mutated targets in tumors and the weakened body’s immune system simultaneously, exerting maximum effects of the medical intervention.

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