Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in adults. Current treatment options typically consist of surgery followed by chemotherapy or more frequently radiotherapy, however, median patient survival remains at just over 1 year. Therefore, the need for novel curative therapies for GBM is vital. Characterization of GBM cells has contributed to identify several molecules as targets for immunotherapy-based treatments such as EGFR/EGFRvIII, IL13Rα2, B7-H3, and CSPG4. Cytotoxic T lymphocytes collected from a patient can be genetically modified to express a chimeric antigen receptor (CAR) specific for an identified tumor antigen (TA). These CAR T cells can then be re-administered to the patient to identify and eliminate cancer cells. The impressive clinical responses to TA-specific CAR T cell-based therapies in patients with hematological malignancies have generated a lot of interest in the application of this strategy with solid tumors including GBM. Several clinical trials are evaluating TA-specific CAR T cells to treat GBM. Unfortunately, the efficacy of CAR T cells against solid tumors has been limited due to several factors. These include the immunosuppressive tumor microenvironment, inadequate trafficking and infiltration of CAR T cells and their lack of persistence and activity. In particular, GBM has specific limitations to overcome including acquired resistance to therapy, limited diffusion across the blood brain barrier and risks of central nervous system toxicity. Here we review current CAR T cell-based approaches for the treatment of GBM and summarize the mechanisms being explored in pre-clinical, as well as clinical studies to improve their anti-tumor activity.
This work reports the effective antitumor activity of patient-derived cytokine-induced killer (CIK) cells against autologous chemo-resistant melanoma Cancer Stem Cells (CSCs).CSCs are clinical relevant targets, associated with disease relapse. We demonstrate that chemotherapy kills indeed proliferating melanoma cells but spares tumorigenic CSCs, in vitro and in vivo. The MHCindependent immunotherapy with CIK cells was proved successful in this challenging framework.Consistent findings were obtained in selected cases of BRAF mutated melanoma treated with small molecule BRAFi. Our data, generated within an autologous system, support the exploration of CIK cells in clinical trials. Cost effectiveness, safety profile and ability to overcome tumor MHC-downregulation are favorable issues to be considered in clinical perspective. CIK cells may be integrated at different levels in the composite therapeutic scenario of metastatic melanoma, offering an additional weapon to control tumor spread and promote its eradication. ABSTRACT PurposeThe MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSCs) was explored, as CSCs are considered responsible for chemo-resistance and relapses. Experimental designPutative mCSCs were visualized by engineering patient-derived melanoma cells (MCs) with a lentiviralvector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays.We explored the sensitivity of eGFP CIK cell activity against chemoresistant mCSCs was confirmed vivo in two distinct immunodeficient murine models. ResultsWe visualized eGFP + mCSCs (14±2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP-positive MCs (1/42) compared with the eGFP-negative counterpart (1/4870).In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells ( ConclusionsThese findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving chemotherapy or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided.
Conflict of interest disclosure: G.D. and S.F. hold a patent on the CSPG4-CAR. G.D. has sponsor research agreements with Bluebird Bio, Cell Medica and Bellicum Pharmaceutical. G.D. serves in the scientific advisory board of MolMed S.p.A and Bellicum Pharmaceutical. The other authors declare no competing financial interests.
We describe a 27 month old female child with partial monosomy for the short arm of chromosome 12: 46,XX,del(12)(p13-1 pl3-3). She differs from the eight cases described by others, in that she is less severely affected. Her main clinical features are developmental delay, protruding tongue, strabismus, slightly unusual facies, slight micrognathia, and speech delay.
Adoptive cell therapy utilizing T cells genetically modified to express a chimeric antigen receptor (CAR) has demonstrated promising clinical results in hematological malignancies. However, solid cancers have not seen a similar success due to multiple obstacles. Investigating these escape mechanisms and designing strategies to counteract such limitations is crucial and timely. Growing evidence in the literature supports the hypothesis that radiotherapy has the potential to enhance the susceptibility of solid tumors to CAR T cell therapy, by overcoming mechanisms of resistance. Radiation treatment can increase the susceptibility of different types of solid cancers (TNBC, HNSCC, PDAC) to B7-H3 CAR T cell-mediated eradication. Multiple mechanisms, including reduced cancer cell proliferation, upregulation of the targeted antigen, modulation of apoptotic molecules may contribute to this signal. The information in the literature and the results we describesupport the ability of radiotherapy to improve the efficacy of CAR T cell therapy in solid tumors.
Cancer adoptive cell therapy (ACT) with HLA-independent tumor killer lymphocytes is a promising approach, with intrinsic features potentially addressing crucial tumor-escape mechanisms of checkpoint inhibitors. Cytokine-induced Killer (CIK) and Natural Killer (NK) lymphocytes share similar tumor-killing mechanisms, with preclinical evidence of intense activity against multiple solid tumors and currently testing in clinical studies. To improve the effective clinical translation of such ACT approaches, several fundamental questions still need to be addressed within appropriate preclinical contexts, capable of overcoming limitations imposed by most traditional two-dimensional assays. Here, we developed a novel experimental approach to explore, dissect, and visualize the interactions of CIK and NK lymphocytes with melanoma tumors in vitro in 3D. Primary melanoma cells were assembled into small tumors that were dispersed in a 3D matrix and challenged with patient-derived CIK or the NK-92 cell line. By means of imaging-based methods, we reported, visualized, and quantitatively measured the recruitment of CIK and NK on the 3D targets, their infiltration, and cytotoxic activity. Our results support the effective tumor recruitment and tumor infiltration by CIK and NK. Such features appeared dependent on the specific geometric aspects of the environment but can be explained in terms of directional migration toward the tumor, without invoking major feedback components. Overall, our 3D platform allows us to monitor the processes of tumor recruitment, infiltration, and killing by means of live measurements, revealing important kinetic aspects of ACT with CIK and NK against melanoma.
Purpose of this study is to explore the preclinical efficacy of Chondroitin Sulfate Proteoglycan 4 (CSPG4)-specific CAR-engineered Cytokine-Induced Killer lymphocytes (CIK) to eradicate melanoma cells with defective HLA class I (HLA-I). The latter abnormality plays a major role in clinical resistance to Checkpoint Inhibitors (CI). CSPG4 was selected as the target because of its high expression on melanoma and its restricted distribution in normal tissues. Our approach is based on CAR.CIK redirected against CSPG4. CIK, ex vivo expanded T-NK lymphocytes endowed with intrinsic HLA-independent antitumor activity, were used as effectors. Experimental procedure. CAR.CIK were generated by retroviral transduction of patient derived PBMC with a vector encoding a 2nd generation CSPG4-CAR with 4-1BB co-stimulation. Surface HLA-I expression was evaluated by flow cytometry on melanoma cell lines (Mel), derived by surgical biopsies. These cells also served as targets for CSPG4 CAR.CIK. The activity of CSPG4 CAR.CIK was analyzed in vitro and in immunodeficient mice grafted with a patient-derived HLA-defective melanoma. Mice were treated intravenously with 3x106 CAR.CIK (5 cells infusions in total). Results. CAR.CIK were efficiently generated from 4 melanoma patients. Mean expression of CSPG4-CAR was 48±8%, the rate of ex vivo expansion (84 fold) and phenotypic characteristics (CD3+CD8+=71±13%, CD3+ CD56+=22.5±13%, NKG2D+= 68±32.3%) were comparable with unmodified controls. Membrane HLA-I molecules were detected in 23/24 Mel samples, with a variable membrane density per cell (median 21232, range 787-49871). Sample Mel17 did not express HLA-I because of a start lost mutation (p.Met1Ile) in β2microglobulin. CSPG4 was intensely expressed by all Mel (78±5%), with no correlation to HLA-I levels. CSPG4 CAR.CIK efficiently killed 10 Mel samples in vitro, including Mel17 (HLA-I negative) and 2 Mel with the lowest HLA-I density (Mel71, Mel72). Mean Mel-specific killing by CSPG4 CAR.CIK was significantly higher compared with unmodified CIK especially at low effector/target (E/T) ratios (85% vs 40% at E/T=1:1; 46% vs 9% at E/T=1:8, p<0.0001). In vivo, CSPG4 CAR.CIK caused a significant inhibition of the HLA-negative Mel17 tumor growth (p<0.0001) as compared to controls. Antitumor activity was confirmed by the reduction of tumor weight and metabolic activity (by fluorescent glucose uptake) measured on the residual explanted tumors. Antitumor response persisted up to 2 weeks after end of the treatment. Conclusions. We reported the activity of CSPG4 CAR.CIK against melanoma, including those with low or defective HLA-I expression. CIK may provide a valid platform for CAR-based strategies against melanoma and solid tumors in general. Our data provide the rationale to implement clinical studies exploring the proposed strategy in melanoma patients not responding or relapsing after immunotherapy with CI. Citation Format: Giulia Cattaneo, Lidia Giraudo, Loretta Gammaitoni, Ilenia Iaia, Fabrizio Carnevale-Schianca, Alberto Pisacane, Enrico Berrino, Caterina Marchiò, Luca Paruzzo, Andrea Michela Biolato, Chiara Donini, Marco Basiricò, Elisa Landoni, Soldano Ferrone, Valeria Leuci, Massimo Aglietta, Gianpietro Dotti, Dario Sangiolo. CSPG4-specific CAR.CIK lymphocyte-based immunotherapy to eliminate HLA class I-defective melanoma tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2812.
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