Genetic redirection of T cells for cancer therapy

Abstract

Adoptive immunotherapy can induce dramatic tumor regressions in patients with melanoma or viral-induced malignancies, but extending this approach to many common cancers has been hampered by a lack of naturally occurring tumor-specific T cells. In this review, we describe recent advances in the genetic modification of T cells using genes encoding cell-surface receptors specific for tumor-associated antigen. Using genetic modification, the many functional properties of T cells, including cytokine secretion and cytolytic capacity, are redirected from their endogenous specificity toward the elimination of tumor cells. Advances in gene design, vectors, and cell production are discussed, and details of the progress in clinical application of this approach are provided.

Autoimmunity associated with immunotherapy of cancer

“…CAR-modified T cells have been used in clinical trials for a range of cancers, including ovarian cancer, neuroblastoma, colon cancer, and lymphoma. 13 The use of CAR-modified T cells is in its infancy, and only limited antitumor effects have been described to date. Nevertheless, in a phase 1 study for renal cell carcinoma (RCC) targeting the TAA carbonic anhydrase IX, adoptive transfer of gene-modified T cells led to grade 3 to 4 liver toxicity in 3 of 7 patients treated.…”

Immunology in the clinic review series; focus on cancer: double trouble for tumours: bi-functional and redirected T cells as effective cancer immunotherapies

“…These domains may enhance flexibility and dimerization of the receptor [23][24][25]. There is some evidence that these domains can engage other cells such as macrophages or natural killer (NK) cells by binding via the Fc receptor leading to a proinflammatory response irrespective of CAR binding, although this can be minimized by modifying the [19,22] Add cysteine residues in the C region of the introduced TCR-ab chains [19] Promotes preferential pairing of introduced TCR-ab chains [13].…”

“…However, a single patient treated with a Her2/neu-specific CAR with a CD28-CD3z signalling domain died as a result of on-target toxicity, resulting in a cytokine storm and subsequent organ failure [39]. On-target toxicity was also observed in a European trial This then attaches to a CD28 transmembrane domain (TM) [23][24][25]. The cytoplasmic domain is composed of the CD3-z signalling element, although other elements may also be included, such as CD28 and 4-1BB motifs which give improved activation and survival [23][24][25].…”

“…The transfer is usually preceded by intensive chemotherapy known as conditioning. This functions to 'make space' for the newly administered cells by reducing the number of host lymphocytes (including Tregs) which compete with the newly transferred cells for homeostatic cytokines [23]. The transfused redirected or bi-functional T cell numbers should increase rapidly in the patient through homeostatic expansion via IL-7 and IL-15 [23], although this expansion may be compromised by high tumour burdens [37].…”

Engineered Drug Resistant Cell-Mediated Immunotherapy

“…Several vector systems have been designed to introduce the chimeric receptors into T cells. Such systems include γ-retroviral vectors, lentiviral vectors and transposon based (sleeping beauty) constructs (Hackett et al, 2010;Westwood & Kershaw, 2010). CAR based anti-neoplastic cellular therapy can be applicable to patients with any HLA type since CARs use antibodies as the component that recognize the target antigen and thereby the CAR-modified cells act in "HLA non-restricted" fashion to destroy their target.…”