Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity

Donia, Marco; Andersen, Rikke; Kjeldsen, Julie Westerlin; Fagone, Paolo; Munir, Shamaila; Nicoletti, Ferdinando; Andersen, Mads Hald; Straten, Per thor; Svane, Inge Marie

doi:10.1158/0008-5472.can-14-2956

Cited by 100 publications

(96 citation statements)

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“…Additionally, a high proportion of both CD4 + and CD8 + T cells expressed CD28, associated with an early or intermediate phenotype of the TILs [25]. To our knowledge, it is not well established to what extent the culture process used for generating T cells for current ACT protocols affects the phenotype or functionality of TILs, though we recently reported that the relative distribution of T cells expressing known antitumor functions seems maintained at stable levels [26]. Several groups have, however, reported that the tumour microenvironment induces T cell unresponsiveness towards tumour cells, which is apparent by high T cell expression of inhibitory markers [17], [20], [27], which could point to a similarity between the phenotype of tumour infiltrating lymphocytes in vivo and after expansion in vitro .…”

Section: Discussionmentioning

confidence: 99%

Influence of ipilimumab on expanded tumour derived T cells from patients with metastatic melanoma

et al. 2017

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IntroductionTumour infiltrating lymphocyte (TIL) based adoptive cell therapy (ACT) is a promising treatment for patients with advanced melanoma. Retrospective studies suggested an association between previous treatment with anti-CTLA-4 antibodies and long term survival after subsequent ACT. Thus, we hypothesized that treatment with anti-CTLA-4 antibodies can induce favourable changes to be detected in TILs.ResultsExpanded T cells from Ipilimumab treated patients had a higher proportion of cells expressing CD27, intracellular CTLA-4, TIM-3 and LAG-3. In addition, broader and more frequent T cell responses against common tumour antigens were detected in patients treated with Ipilimumab as compared to anti-CTLA-4 naïve patients.Materials and methodsExpanded TILs were obtained from patients with advanced melanoma who had received Ipilimumab in the previous six months, or had not received any type of anti-CTLA-4 antibody. T cell specificity and expression of phenotypic and exhaustion markers were scrutinized as well as functional properties.ConclusionsIpilimumab may induce tumor-infiltration of T cells of a more naïve phenotype expressing markers related to activation or exhaustion. Additionally, Ipilimumab may increase the frequency of T cells recognizing common tumour associated antigens.

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Section: Discussionmentioning

confidence: 99%

Influence of ipilimumab on expanded tumour derived T cells from patients with metastatic melanoma

et al. 2017

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“…The expression of HLA class II has been suggested to represent an immune escape mechanism for melanoma. 45 The retargeting of CD8 C CTLs with HLA class II restricted TCRs may counter this mechanism of tumor escape. TCRs C13 and D71 recognized epitopes naturally processed from a 173 aa hTERT fragment, as described above.…”

Section: Discussionmentioning

confidence: 99%

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

et al. 2016

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We herein report retargeting of T-helper (Th) cells against the universal cancer antigen telomerase for use in adoptive cell therapy. The redirected Th cells may counter tumor tolerance, transform the inflammatory milieu, and induce epitope spreading and cancer senescence. We have previously conducted a series of trials evaluating vaccination with telomerase peptides. From long-term survivors, we isolated >100 CD4 C Th-cell clones recognizing telomerase epitopes. The clones were characterized with regard to HLA restriction, functional avidity, fine specificity, proliferative capacity, cytokine profile, and recognition of naturally processed epitopes. DP4 is the most prevalent HLA molecule worldwide. Two DP4-restricted Tcell clones with different functional avidity, C13 and D71, were selected for molecular T-cell receptor (TCR) cloning. Both clones showed a high proliferative capacity, recognition of naturally processed telomerase epitopes, and a polyfunctional and Th1-weighted cytokine profile. TCR C13 and D71 were cloned into the retroviral vector MP71 together with the compact and GMP-applicable marker/suicide gene RQR8. Both TCRs were expressed well in recipient T cells after PBMC transduction. The transduced T cells co-expressed RQR8 and acquired the desired telomerase specificity, with a polyfunctional response including production of TNFa, IFNg, and CD107a. Interestingly, the DP4-restricted TCRs were expressed and functional both in CD4C and CD8 C T cells. The findings demonstrate that the cloned TCRs confer recipient T cells with the desired hTERT-specificity and functionality. We hypothesize that adoptive therapy with Th cells may offer a powerful novel approach for overcoming tumor tolerance and synergize with other forms of immunotherapy.

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“…In two cases, one patient with CR (M42) and one patient with no evidence of tumor regression (M40) where autologous melanoma cell lines were not available, single-cell suspensions obtained from enzymatically digested tumor fragments were used in antitumor reactivity assays (standard digestion protocol, as described previously; ref. 30). In all other cases where autologous tumor cell lines were not available, TILs were tested against multiple (5-12) HLA-A-matched allogeneic melanoma cell lines, and the highest level of reactivity to any of the cell lines was reported.…”

Section: Immunologic Analysesmentioning

confidence: 99%

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

Andersen

Donia

Ellebæk

et al. 2016

Clinical Cancer Research

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Purpose: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen.Experimental Design: Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625).Results: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment.Conclusions: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2.

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Aberrant Expression of MHC Class II in Melanoma Attracts Inflammatory Tumor-Specific CD4+ T- Cells, Which Dampen CD8+ T-cell Antitumor Reactivity

Cited by 100 publications

References 44 publications

Influence of ipilimumab on expanded tumour derived T cells from patients with metastatic melanoma

Influence of ipilimumab on expanded tumour derived T cells from patients with metastatic melanoma

T-helper cell receptors from long-term survivors after telomerase cancer vaccination for use in adoptive cell therapy

Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen

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