Adoptive cell transfer therapy with ex vivo primed peripheral lymphocytes in combination with anti-PDL1 therapy effectively inhibits triple-negative breast cancer growth and metastasis.

BACKGROUND: Adoptive cell transfer cancer immunotherapy holds promise for treating disseminated disease, yet generating sufficient numbers of lymphocytes with anti-cancer activity against diverse specificities remains a major challenge. We recently developed a novel procedure (ALECSAT) for selecting, expanding and maturating polyclonal lymphocytes from peripheral blood with the capacity to target malignant cells. METHODS: Immunodeficient mice were challenged with triple-negative breast cancer cell lines or patient-derived xenografts (PDX) and treated with allogeneic or autologous ALECSAT cells with and without anti-PDL1 therapy to assess the capacity of ALECSAT cells to inhibit primary tumor growth and metastasis. RESULTS: ALECSAT mono therapy inhibited metastasis, but did not inhibit primary tumor growth or prolong survival of tumor-bearing mice. In contrast, combined ALECSAT and anti-PDL1 therapy significantly inhibited primary tumor growth, nearly completely blocked metastasis, and prolonged survival of tumor-bearing mice. CONCLUSIONS: Combined ALECSAT and anti-PDL1 therapy results in favorable anti-cancer responses in both cell line-derived xenograft and autologous PDX models of advanced triple-negative breast cancer.

A randomized phase II trial of efficacy and safety of the immunotherapy ALECSAT as an adjunct to radiotherapy and temozolomide for newly diagnosed glioblastoma.

BACKGROUND: There is an urgent need for effective treatments against glioblastoma (GBM). In this trial, we investigated the efficacy and safety of an adoptive cell-based immunotherapy. METHODS: Patients with newly diagnosed GBM were recruited at 4 study sites in Sweden. The patients were randomized 1:2 to receive either radiotherapy (RT), 60 Gy/30 fractions, with concomitant and adjuvant temozolomide (TMZ) only, or RT and TMZ with the addition of Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT) in an open-label phase II trial. The primary endpoint was investigator-assessed progression-free survival (PFS). The secondary endpoints were survival and safety of ALECSAT. RESULTS: Sixty-two patients were randomized to either standard of care (SOC) with RT and TMZ alone (n = 22) or SOC with ALECSAT (n = 40). Median age was 57 years (range 38-69), 95% of the patients were in good performance status (WHO 0-1). There was no significant difference between the study arms (SOC vs ALECSAT + SOC) in PFS (7.9 vs 7.8 months; hazard ratio [HR] 1.28; 95% confidence interval [CI] 0.70-2.36; P = .42) or in median overall survival (OS) (18.3 vs 19.2 months; HR 1.16, 95% CI 0.58-2.31; P = .67). The treatment groups were balanced in terms of serious adverse events (52.4% vs 52.5%), but adverse events ≥grade 3 were more common in the experimental arm (81.0% vs 92.5%). CONCLUSION: Addition of ALECSAT immunotherapy to standard treatment with radiochemotherapy was well tolerated but did not improve PFS or OS for patients with newly diagnosed GBM.

Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells.

In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

Cancer/testis antigens: structural and immunobiological properties.

Characterization of tumor-associated antigens recognized by cytotoxic T lymphocytes which has evolved during recent years opens new possibilities for specific anti-cancer immunotherapy. Among different groups of tumor-associated antigens, cancer/testis (CT) antigens (expressed in many tumors and among normal tissues only in testes) represent the most perspective antigens for immunotherapy because of their broad tumor-specific expression. More than 50 CT antigens have been described so far and, for many of them, epitopes recognized by T lymphocytes have been identified. The most studied group of CT antigens is the MAGE proteins, which form the so-called MAGE superfamily, together with some MAGE-like proteins that have a different distribution than classical CT antigens. The MAGE superfamily includes five families: MAGE-A, MAGE-B, MAGE-C, MAGE-D, and necdin. Comparison of the structure of members of MAGE superfamily points to the existence of a domain organization of these proteins. The central, core domain (second domain) is highly conservative. The first domain is homologous among MAGE family members with a CT expression, but unique for each member of the MAGE-D and necdin families. In addition to the homology of the central domain, the third domain is also homologous among all members of MAGE superfamily, but to a much lesser extent. The MAGE-D proteins contain an additional, fourth domain, which in the case of MAGE-D3 coincides with trophinin, a separate molecule described previously as an adhesion molecule that participates in embryo implantation. The structural classification of the members of MAGE superfamily might help in the future to understand the biological function of MAGE proteins. One important property of the CT antigens is the up-regulation of their expression by DNA demethylating agents, indicating a possible mechanism for their re-expression in tumors. One of the implications of this particular property could be that a combination of immunotherapy targeting CT antigens with chemotherapy inducing up-regulation of CT antigens might result in more efficient tumor eradication.