Melanoma: Critical Debates (Challenges In)

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A first phase I trial showed improved response with increased frequencies in partial and complete remission Besser et al. All trials were performed under myeloablative conditions and IL-2 administration based on the rationale to provide space and stimuli for homeostatic expansion of adoptively transferred T cells.

Tumor infiltrating lymphocytes TIL are isolated from a melanoma lesion, amplified ex vivo and re-administered without further modification. While adoptive transfer of TILs is showing promising efficacy in first trials, attempts are made to redirect blood T cells with pre-defined specificity toward melanoma. The rationale for using effector T cells from the peripheral blood is provided by the frequent inability to isolate TILs in sufficient amounts from a given melanoma lesion and the more progressed proliferative stage of TILs compared to blood T cells. To redirect peripheral blood T cells specifically towards melanoma antibodies were combined in a bi-specific antibody format which targets T cells with by an anti-CD3 antibody as one arm and the melanoma cell with the other arm.

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Upon application it is assumed that bi-specific antibodies build a bridge between T cells and melanoma cells thereby forcing peripheral blood cytolytic effectors towards their target. Bi-specific antibodies were directed against melanoma p97, gp Cochlovius et al. Therapeutic potency was demonstrated by long-term survival in pre-clinical models resulting, the efficacy, however, critically depends on the number of recruitable effector cells at the tumor site.

Bi-specific constructs triggering CD28 costimulation of T cells furthermore increased tumor-cell killing predominantly by recruiting cytolytic cells without targeted specificity Grosse-Hovest et al. While first generation bi-specific reagents were conventional hetero-dimeric antibodies, second generation antibodies are constituted of two single polypeptide chain antibodies covalently joined by a linker domain Grosse-Hovest et al.

Those so-called bi-specific T cell engager BiTE antibodies targeting CD3 on T cells and a tumor-associated antigen on malignant cells of solid tumors showed efficacy even in nano-molar concentrations in a clinical trial Bargou et al. The size of antigen as well as the targeted epitope impacts the efficacy in T cell activation since a BiTE antibody targeting the membrane proximal domain of HMW-MAA on melanoma cells showed more potent than those binding to more distal domains Bluemel et al.

The same observations were made when targeting EpCAM indicating that there is obviously a correlation between epitope positioning relative to the cell membrane and the potency in T cell activation. Technical advances in genetically engineering blood T cells ex vivo fueled efforts to design T cells with pre-defined specificity for redirected targeting melanoma cells. Recombinant DNA technology and the structural elucidation of the T cell receptor TCR complex together with recent developments in vector design made the genetic T cell modification with a recombinant TCR feasible.

The melanoma gp specific TCR was one of the first be cloned from T cells accumulating at the tumor site. TCR modified T cells were amplified ex vivo and re-infused in therapeutic doses to the patient Figure 1. In the Rosenberg group published the first clinical trial using T cells with engineered specificity for melanoma. Adoptive transfer of those T cells caused a strong response against metastases in distant organs.

Engineered T cells persisted in circulation of most patients for nearly 2 months. The therapeutic efficacy, however, was disappointingly low with 2 out of 17 patients showing objective regression of metastases resulting in complete response. In those patients, interestingly, engineered T cells were detected in the blood for a year after treatment implying that therapeutic efficacy may correlate with long-term anti-melanoma immunity Morgan et al.

In a very recent trial, similarly TCR engineered T cells showed efficacy towards brain metastases of melanoma indicating that this procedure may be useful to treat otherwise incurable metastatic sites Hong et al. Although these and other trials showed technical feasibility in engineering TCR modified T cells and clinical practicability in the adoptive transfer of those cells, the unexpected low clinical response raised concerns with respect to clonal variability of the targeted melanoma lesion. Melanoma like other malignant diseases displays clonal evolution during tumor progression which enables the tumor to evade T cell recognition.

As a consequence TCR engineered T cells are no longer able to recognize and destroy those melanoma cells with mutant or lack of MHC-peptide complexes. Limitations in the expression of a recombinant TCR in T cells additionally dampened enthusiasm in the strategy.

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Co-expression of a recombinant TCR together with the physiological TCR in T cells turned out to create new but unpredictable specificities which may result in severe auto-reactivity. In mouse models hetero-dimer formation resulted in severe auto-immunity Bendle et al. Tremendous efforts were undertaken to solve the problem including replacement of TCR constant domains by homologous murine domains Cohen et al.


The Great Debate at “Melanoma Bridge”, Napoli, December 2nd, 2017

Zelig Eshhar pioneered the strategy in generating a chimeric antigen receptor CAR molecule composed of an extracellular single chain antibody for binding and an intracellular TCR signaling domain Eshhar et al. Due to the modular design a nearly unlimited variety of antigens can be targeted as long as an antibody is available, including non-classical T cell antigens like carbohydrates as HMW-MAA, also called MCSP Reinhold et al.

Along with multiple other modifications the stability of expression and antigen binding has been substantially improved during the last years Bridgeman et al.

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