Lenalidomide Augments the Antitumor Activities of Eps8 Peptide-Specific Cytotoxic T Lymphocytes against Multiple Myeloma

Abstract

Cancer immunotherapy is a promising new approach to cancer treatment. It has been demonstrated that a high number of tumor-specific cytotoxic T cells (CTL) is associated with increased survival in patients with multiple myeloma. Here, we focused on EGFR pathway substrate 8 (Eps8) as a candidate tumor-associated antigen (TAA) in multiple myeloma. Previous work has shown that Eps8-based immunotherapy in HLA-A2 þ cancer patients may result in efficient antitumor immune responses against diverse tumor types. To improve immunotherapy for patients with multiple myeloma, we constructed a cocktail vaccine by combining several HLA-A2-restricted epitopes derived from Eps8 (Eps8 cocktail), including Eps8 101-2L (WLQDMILQV), Eps8 276-1Y9V (YLDDIEFFV), and Eps8 455-1Y (YLAESVANV). The CTLs induced by Eps8 cocktail (Eps8 cocktail-CTLs) showed highly effective anti-multiple myeloma activity, including Th1 cytokines production, cell proliferation, and cytotoxicity against HLA-A2 þ multiple myeloma cells. This study highlights the importance of using a cocktail vaccine instead of a single-peptide vaccine to induce a robust response. Importantly, we revealed that lenalidomide effectively stimulated the antitumor activity of the Eps8 cocktail-CTLs, with increasing expression trends for T-cell markers (CD28, CD40L, 41BB, and OX40). Compared with unstimulated CTLs and Eps8 cocktail-CTLs, lenalidomide-treated Eps8 cocktail-CTLs showed superior anti-multiple myeloma activity in humanized multiple myeloma models, including delaying tumor burden increases due to enhanced immune function. These results provide the framework for an Eps8 cocktail vaccination therapy to induce effective Eps8-specific CTLs in HLA-A2 þ patients with multiple myeloma. Moreover, these studies further demonstrate that lenalidomide augments the immune response, providing a possibility for its use in combination with peptide vaccines to improve patient outcomes.

Identification of HLA‐restricted Cytotoxic T Lymphocyte Epitopes of B Cell Maturation Antigen as Promising Peptide Vaccine Candidates for Preventive and Therapeutic Strategies in Multiple Myeloma

“…[12][13][14] Peptide-based treatments, either as monotherapy or in combination with other treatment modalities, have exhibited robust induction of peptide-specific immune responses and clinical benefits in MM. [15][16][17][18][19] Phase I and II clinical studies have demonstrated that peptide vaccines based on MM-associated antigens are well-tolerated and capable of eliciting antigen-specific T cell responses, either for preventing the progression of smoldering multiple myeloma (SMM) to active MM or reducing the relapse rate following ASCT. [15,16] In murine MM models, treatment with an HLA-A*02:01-restricted peptide vaccine derived from multiple myeloma special antigen-1 and Dickkopf-1 resulted in tumor volume reduction, attenuation of bone destruction, and significant improvement in survival.…”

Anti‐angiogenic therapy enhances cancer immunotherapy: Mechanism and clinical application

“…81 These ACTs are primarily used for the treatment of hematological malignancies. 46,47,82,83 Limited lymphocyte infiltration and immunosuppressive microenvironment, which are associated with abnormal tumor vasculature, are major challenges to the effectiveness of ACT in solid tumors.…”

“…Limited or absence of T-cell infiltration within tumors is a significant factor that compromises the effectiveness of various immunotherapies, such as ICIs and ACT therapy. 82,89 The tumor vasculature plays a crucial role as the entry point for circulating leukocytes, 44 and therefore, abnormal vessels within tumor tissues may contribute to the immune escape of tumor cells. 84,90 Mechanistically, the abnormal vascular structure contributes to compromised lymphocyte infiltration.…”

“…183 This combination therapy also attenuated tumor growth and progress in lymphoma 89 and myeloma xenografts. 82,89 Furthermore, lenalidomide combined with DNA vaccine decreased the presence of myeloid-derived suppressor cells and Treg cells. 184 These preclinic investigations provide further rationale for clinical application.…”

The long multi-epitope peptide vaccine combined with adjuvants improved the therapeutic effects in a glioblastoma mouse model

“…Although lenalidomide has been shown to improve progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM) (9), the effects of lenalidomide alone have not been shown in GBM. Lenalidomide had little effect on the induction of apoptosis in GBM cells; however, it regulated the functions of CAR T cells and improved patient outcomes in combination with peptide vaccines in previous studies (10)(11)(12). The combination of the peptide vaccine and an antiprogrammed cell death protein 1 (PD1) antibody therapy worked synergistically against GBM in a previous study (13).…”