Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen

Abstract

Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/ melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA ؊ and CD45RO ؉ after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA ؉ and CD45RO ؊ phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss.

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

“…Adding NS5 T cells might be an advantage when reconstituting a multispecific antiviral T cell response in vivo to avoid the potential overkilling of hepatocytes; however, the ultimate answer to which of the T cells are more beneficial remained to be evaluated in vivo. With regard to the tolerability of mouse TCR, it was recently reported that mouse TCR are well tolerated in vivo (38,39). In the melanoma trial (39), it was shown that patient lymphocytes transduced with highly reactive mouse or human antitumor TCRs mediated cancer regression in 19 and 30%, respectively, of melanoma patients.…”

“…With regard to the tolerability of mouse TCR, it was recently reported that mouse TCR are well tolerated in vivo (38,39). In the melanoma trial (39), it was shown that patient lymphocytes transduced with highly reactive mouse or human antitumor TCRs mediated cancer regression in 19 and 30%, respectively, of melanoma patients. In that study, both mouse-and human TCR-transduced cells traffic to and destroy melanoma tumors in the patients.…”

Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response

“…[1][2][3][4] Patient-derived T cells are retrovirally engineered ex vivo to express a recombinant T-cell receptor or, alternatively, a chimeric antigen receptor (CAR, immunoreceptor), amplified and re-infused to recognize and to destroy tumour lesions by their cytolytic capacities. In contrast to recombinant T-cell receptors, CARs consist of a single polypeptide chain with an antibody-derived single chain fragment (scFv) in the extracellular moiety for binding and the CD3z or combined CD28-CD3z signalling domain in the intracellular moiety for T-cell activation.…”

Dendritic cells in cancer immunotherapy

“…In addition, somatically mutated antigens, which are associated with regression and long-term survival [3,4], should be tested, as well as antigens relevant for the oncogenic phenotype (mutated and viral oncogenes, certain non-mutated antigens that tumors overexpress) to diminish antigen loss and escape [5,6]. Side effects observed recently with adoptive T-cell therapy [7] suggest that tumor-specific antigens (such as cancer testis or mutated antigens, or Muc-1) [5,6,8] should be prioritized to avoid similar toxicity with highly immunogenic cancer vaccines of the future. In addition, it appears mandatory to block some of the immunosuppressive circuits and to enhance migration of T cells into tumor sites in order to make cancer vaccines more clinically effective [9].…”