Autoimmune B-cell lymphopenia after successful adoptive therapy with telomerase-specific T lymphocytes

Abstract

IntroductionAttempts to treat experimental tumors with adoptive T lymphocyte transfer started in 1960, soon after the demonstration that the cellular arm of the immune system was responsible for tissue rejection. 1 The translation of this approach to the clinic, however, became possible when human tumor-infiltrating lymphocytes (TILs) could be expanded in vitro and injected back into cancer patients. 2 Only recently, however, an objective cancer regression was achieved in approximately 50% of patients with metastatic tumor after the introduction of host preconditioning by lymphodepletion before the treatment, followed by high-dose interleukin-2 (IL-2) to sustain in vivo expansion of T cells. 3,4 So far, this approach has been limited to melanoma patients, from whom TILs of known specificity are easily cultured in vitro, whereas for tumors other than melanoma the rescue of TILs is problematic.Telomerase is considered an attractive target as universal antigen for the immunotherapy of cancer. Telomerase reverse transcriptase (TERT) is the protein component of the telomerase complex responsible for elongation of telomeres and plays an essential role in sustaining cancerous cell proliferation. 5 TERT is silent in most human somatic tissues but reactivated in 85% of tumors. Active immunization against telomerase and cancer vaccination clinical trials have been attempted that demonstrate little toxicity, but results concerning therapeutic efficacy are not conclusive. 6,7 Although T lymphocytes against telomerase were isolated and extensively characterized in vitro, 8,9 the use of adoptive cell therapy (ACT) with telomerase-specific lymphocytes has never been investigated. To evaluate therapeutic efficacy and determine the potential immunopathology associated with TERT-based ACT, we generated and analyzed the activity of TERT-specific CD8 ϩ T cells. Methods Mice and cell linesC57BL/6 mice were from Charles River Laboratories Inc. Transgenic adenocarcinoma mouse prostate (TRAMP) mice, a gift from N. M. Greenberg (Fred Hutchinson Cancer Research Center), were maintained in the mouse facility of Istituto Oncologico Veneto. Heterozygous TRAMP used in the experiments were obtained and screened as described. 10 C57BL/6-CD45.1 ϩ mice were a gift from M. P. Colombo (National Institutes of Tumors), pmel-1 TCR transgenic mice were a gift from N. Restifo (National Institutes of Health), and human leukocyte antigen (HLA)-A*0201-transgenic (HHD) mice were obtained by F. A. Lemonnier (Institut Pasteur) and maintained at Istituto di Ricerca di Biologia Molecolare. Rag2 Ϫ/Ϫ ␥ c Ϫ/Ϫ were purchased form Taconic. Mice were treated in accordance with European guidelines (http://ec.europa.eu/environment/chemicals/ lab_animals/legislation_en.htm). B16 melanoma cells were provided by N. Restifo (NIH). B16-B7.1 cells, genetically modified to express mouse B7.1 (provided by P. Della Bona, Istituto Scientifico San Raffaele) were cultured in the An Inside Blood analysis of this article appears at the front of this issue.The online version of thi...

Tumor Ablation by Gene-Modified T Cells in the Absence of Autoimmunity

“…Despite these reports, several studies have reported mild to severe autoimmune toxicity following transfer of tumor reactive T cells (33)(34)(35) including liver toxicity in patients involving transfer of T cells gene-modified with an anti-CAIX scFv receptor (13). Toxicity, manifested by increased levels of transaminase in serum, was thought to be due to CAIX expression on bile duct epithelium.…”

Feasibility of Telomerase-Specific Adoptive T-cell Therapy for B-cell Chronic Lymphocytic Leukemia and Solid Malignancies

“…Alternatively, TCR can be isolated from mouse CTLs primed in vivo by vaccination of transgenic mice bearing human HLA-A2 molecules (14,15), an approach that was recently improved by the immunization of human antigen-negative mice engineered to bear the whole human TCR-a and b gene loci together with the HLA-A2 allele (16). We previously reported the feasibility to isolate and enrich a polyclonal T-cell population specific for human telomerase (hTERT) [865][866][867][868][869][870][871][872][873] epitope through in vitro stimulation of mouse T lymphocytes isolated from HLA-A2.1 transgenic mice (17). These CTLs recognized different hTERT-expressing human cancer cell lines, as well as colon cancer stem cells (17).…”

“…We previously reported the feasibility to isolate and enrich a polyclonal T-cell population specific for human telomerase (hTERT) [865][866][867][868][869][870][871][872][873] epitope through in vitro stimulation of mouse T lymphocytes isolated from HLA-A2.1 transgenic mice (17). These CTLs recognized different hTERT-expressing human cancer cell lines, as well as colon cancer stem cells (17). Telomerase is reactivated in the majority of human tumors independently of their histology (18), and several hTERT epitopes, which are naturally processed and presented in association with MHC molecules on tumor cell surface, have been already documented (19)(20)(21)(22).…”

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

“…The CD8 + T cells recognizing the self-antigen mTERT can treat established melanomas as effectively as T cells derived from Pmel-1 TCR transgenic mice, which recognize the hgp-100 melanoma antigen . However, melanoma growth control following ACT with both CD8 + T cells was achieved only in mice completely lacking adaptive immunity, lymphodepleted by nonmyeloablative irradiation, or pretreated with low doses of the chemotherapeutic drug 5-flourouracil (Ugel et al, 2012;Ugel et al, 2010). In normal hosts, mTERT-specific CD8 + T lymphocytes lack therapeutic efficacy and do not induce the appearance of Tip-DCs unless coupled with CSF-1R blockade.…”

“…To test this we used a model where CD8 + T cells have weak reactivity to their cognate antigen and fail to mediate anti-tumor effects in normal mice. We used mouse telomerase (mTERT)-specific CD8 + T cells, which lack anti-tumor activity against the TERT + MCA203 fibrosarcoma when used alone (Ugel et al, 2012;Ugel et al, 2010). Repeated administrations of anti-CSF-1R mAb with mTERT-specific CD8 + T cells on WT mice induced an additive delay in tumor growth ( Figure S6B and Figures 6B).…”