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.

Five-Year View

The near future will witness an explosion of activity in the cancer immunotherapy arena, a major source of future medicine for cancer covering diverse therapeutic platform technologies. Novel immune checkpoint blockade and immune-stimulating agents will be developed and approved as monotherapies or as adjuncts to targeted therapies in metastatic disease. We will also witness the development and licensure of the first wave of T-cell-based immune interventions and bispecific engineered antibodies, more likely first in leukemias and lymphomas where there are fewer immune inhibiting mechanisms to overcome. Vaccines will be predominantly tested in minimal residual disease in various cancer types and as adjunct to other forms of therapy facilitating a safer and more effective treatment. Testing of vaccines will be guided by biomarkers, and we will likely witness the licensure of the first therapeutic vaccine with a comprehensive companion diagnostic. Finally, efforts to develop immune interventions that achieve objective and durable clinical response in individual patients will surpass, for the first time, the activities in support of immunotherapies that only achieve a slowdown of disease progression.

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Acknowledgment
The authors would like to thank Clea Martin and JP Urenda for language editorial support.

Abstract
Cancer Vaccines: What Have We Learned?
Lessons Learned From Other Immune Interventions
Cancer Vaccines: Quo Vadis?
Expert Opinion
Five-Year View
References
Sidebar

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.