Repositioning Therapeutic Cancer Vaccines in the Dawning Era of Potent Immune Interventions

Adrian Bot; Francesco Marincola; Kent A Smith

Expert Rev Vaccines. 2013;12(10):1219-1234.

Abstract

Based on lessons learned with various immune interventions, this review aims to provide a constructive framework for repositioning therapeutic cancer vaccination. Intensive research throughout the past decade has identified key hurdles interfering with the efficacy of cancer vaccines. The vaccination concept still holds promise if positioned appropriately in minimal residual disease and select early disease stage cancer indications. However, in advanced cancer, it must be integrated with complementary immune interventions to ensure reconstruction of a functional immune repertoire and simultaneous blockade of immune inhibiting mechanisms. Vaccination could render complex and integrative immune interventions simpler, safer and more effective. The near future will witness an explosion of activities in the cancer immunotherapy arena, witnessing a rational repositioning of vaccines rather than their extinction.

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Table 1. An immune-functional classification of solid tumors with therapeutic implications.
Category ^†	Presence of TILs or systemic T cells with antitumor activity	Biology	Applicable therapeutic approaches
1. Immunologically involved, established solid tumors	TILs present	1a. TILs mostly reactive against driver oncogenes: kept in check by inhibitory mechanisms	TILs + immune inhibiting checkpoint blockade
		1b. TILs mostly reactive against passenger genes due to lack of immunogenic driver oncogenes and/or deployment of immune response-suppressing mechanisms	Receptor-engineered T cells + checkpoint blockadeorVaccines against driver oncogenes, in combination with immune-stimulating approaches
2. Established solid tumors, immunologically uninvolved	No TILs	Poorly immunogenic tumors or early deployment of immune response-suppressing mechanisms	Receptor-engineered T cells + checkpoint blockade +/- vaccination, or biological response modifiers
3. Minimal residual disease	3a. Systemic immunity present	Inhibiting checkpoints that limit the activity of endogenous T cells	Checkpoint blockade +/- autologous T cells or vaccines
	3b. No systemic immunity	Poorly immunogenic tumors due to immune suppression or limited antigen presentation	Vaccination +/- checkpoint blockadeorReceptor-engineered T cells +/- checkpoint blockade

^† Divided the totality of tumors based on preexisting tumor reactive T cells that could be potentially retrieved, expanded ex vivo and utilized to restore or amplify immune competency. In case of preexisting T-cell immunity, vaccination and checkpoint blockade could complement autologous T-cell therapy. In absence of preexisting T cells that could be retrieved and manipulated, adoptive T-cell therapy with receptor-engineered T cells complemented by other therapies could be applicable. In minimal residual disease when the immune competence is relatively preserved, vaccines could be utilized to generate or amplify immunity against remaining tumor cells, alone or in conjunction with other modalities.
TIL: Tumor-infiltrating lymphocytes.