Genetic immunotherapy

Attempts at enhancing the naturally weak immunogenicity to tumours have resulted from a clearer understanding of antigen recognition, processing and presentation at the molecular level, and in particular, the nature of effector (T cell) responses to antigenic stimulation.

A number of approaches are currently being evaluated: ♦ Systemic immunotherapy for cancer with recombinant cytokine therapy is associated with low response rates at the expense of high systemic toxicity. Small doses of cytokines are delivered at the tumour site by inserting cytokine genes into cultured tumour-

infiltrating lymphocytes (TILs) ex-vivo, then re-infusing the cells. Anti-tumour efficacy of this subset of T cells has been shown to improve with the transfer of the genes for tumour necrosis factor and interleukin-2 (IL-2).

♦ Transducing tumour cells ex-vivo with the same cytokine, allo-geneic HLA (human leucocyte antigen), or genes encoding co-stimulatory molecules, such as the B7 family of genes, prior to re-infusion (after irradiation of eliminate malignant activity) so that T-cell recognition of tumour antigens is enhanced. CTLs recognize tumour-specific antigens presented on the surface of these cells. They are induced by the local secretion of the transferred cytokine gene product to expand, target, and destroy cancer cells.

♦ Polynucleotide (naked DNA) vaccinations (as opposed to previous vaccinations consisting of peptides, whole tumour cells, or tumour cell lysates) have great therapeutic potential in that delivery of genes that express unique oncoproteins (such as KRAS or lymphoma idiotypic protein) endogenously within a cell, may then result in an MHC class I CD8+ response and proliferate activation of CTLs, rather than a less effective class II CD4+ response induced by exogenous peptides. This may be a further means of breaking down immunotolerance to tumours and lead to the generation of tumour-specific responses. Targets for DNA therapy are shown in the table.

The limitation to this approach is the paucity of truly tumour-specific antigens which may be exploited as molecular targets. Most target antigens are tumour-associated (i.e. normal cellular genes inappropriately expressed in cancer) and lack epitopes to activate T cells. However, delivery of genes encoding the E6 and E7 proteins of HPV 16 and 18, in patients with advanced cervical cancer, resulted in antibody and HPV-specific T-cell responses.

♦ Dendritic cells (DCs) are potent antigen-processing and antigen-presenting cells which are critical to the development of primary MHC-restricted T-cell immunity to infectious agents, in autoimmune diseases and anti-tumour immunity. Recent technological advances have allowed their expansion in vitro from peripheral blood precursors and marrow using cytokines. Cultured DCs are able to take up exogenous antigen (as tumour protein, peptide, or RNA), or may be transduced with genes encoding tumour antigen using physical or viral methods of gene transfer, and then present it to T cells to induce a measurable anti-tumour effect.

Early clinical trials have involved DCs pulsed with idiotypic protein for relapsed B-cell lymphoma or whole tumour lysates for melanoma; in both cases antigen-specific immunity has been demonstrated.

Table 41.5 Targets for DNA vaccination strategies

Target

Class of antigen

Associated cancer(s)

p53

Mutated tumour suppressor

>50% all human cancers

RAS

Mutated oncogene product

>10% all human cancers; >80% pancreatic,colorectal

ERBB2

Growth factor receptor

Breast, ovary, stomach, pancreas

Igidiotypes

Idiotypicepitope

B-cell lymphoma

HPVE6, E7

Viral gene products

Cervical cancer

P210BCR/ABL

Mutated oncogene product

Chronic myeloid leukaemia

MAGE-1

Embryonic gene product

Melanoma, breast

Tyrosinase Normal differentiation antigen >50% melanomas

Tyrosinase Normal differentiation antigen >50% melanomas

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