Effective immunotherapy of weakly immunogenic solid tumours using a combined immunogene therapy and regulatory T-cell inactivation

Abstract

Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm 3 tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.

Targeting Regulatory T Cells in Cancer

“…Systemic T Reg depletion in patients induced regression of melanoma metastases (9) and in mice when combined with immunogene stimulation of intratumoural immune effector cells resulted in cure of 90% of animals who had large and weakly immunogenic sarcomas (10). The clinical objective will be to provide sustained reduction of T Reg function, particularly in the tumour environment, allowing enhancement of anti-tumour effector functions and with minimal risk of developing systemic autoimmune diseases.…”

Oral Tolerance to Cancer Can Be Abrogated by T Regulatory Cell Inhibition

“…4b, tumours in mice receiving anti-CD25 Ab eventually regressed completely, both in depletion during tolerisation and permanent depletion groups. We, and others, have previously reported the finding that anti-CD25 administration prior to tumour induction induces complete tumour regression [8].…”

“…We have previously shown that our anti-CD25 Ab administration protocol facilitates 90% inactivation of CD25 + cells over a period of 14 days [8]. Mice were randomised to receive either anti-CD25 Ab at the commencement of the 14-day feeding schedule, and again at the end of feeding (referred to as permanent depletion) or Ab at the time of commencing feeding only (referred to as depletion during tolerising) or control Ab, or no Ab (Fig.…”

“…We have previously shown that growth of the weakly immunogenic JBS cell line in the flank of immune competent mice led to an increase in Treg cell numbers in the tumour environment but not systemically [8]. In this study we have modelled the presence of tumour fragments in the gut to the clinical situation by gavage feeding of JBS cells to mice.…”

Terapia génica: opción terapéutica para neoplasias, infecciones y enfermedades monogénicas

“…Esto disminuiría la anormal tolerancia del tumor y favorecería la inmunidad, tanto contra las células tumorales que expresan B7, como contra las células del tumor original. 46,47 Éstas y otras estrategias se han ensayado frente a diferentes neoplasias, como cáncer de ovario, 48,49 melanoma, 50-52 cáncer de mama, 50 glioblastoma, 53,54 carcinoma hepatocelular 55 y neuroblastoma, 56 entre muchas otras. Cabe destacar que, al día de hoy, los protocolos oncológicos de TG están dirigidos a pacientes con metástasis, más que contra las neoplasias primarias.…”