Table 1.

Comparison of antigen delivery platforms

Modality	Type	Rationale	Benefits	Drawbacks	Relevant citations or trials
Peptide	Neoantigen	Cancers often have mutations in proteins that can be recognized as non-self by T cells	Can target proteins necessary for cancer survival	Patient-specific, difficult to identify neoantigens that would drive strong immune responses	19, 117
	Viral tumor antigen	Viral proteins are highly immunogenic, Sometimes required for tumor growth	Shared across patients, truly foreign, highly immunogenic, often required for carcinogenesis	Not applicable for most cancers	98
	Tumor associated antigen	Many cancers express antigens which would only otherwise be expressed in embryonic or gonadal tissues or lowly expressed in healthy tissues	Shared across patients	Since these are often not required for cancer survival, tumors can down regulate these proteins to evade an immune response	118
Nucleic Acid	DNA	Putative tumor antigens are encoded into DNA constructs which can then be delivered to patients where the antigens are transcribed and translated	Stable and inexpensive mechanism of antigen delivery, intrinsic adjuvanticity as can encode protein adjuvants	Difficulties in transfection, degradation by DNases	99
	mRNA	Putative tumor antigens are encoded into mRNA constructs which can then be delivered to patients where the antigens are directly translated	RNA is highly immunogenic, can encode protein adjuvants	Also, difficulties in transfection, degradation by RNases	60
	Self-amplifying RNA	Viral RNA encodes an RNA polymerase in addition to tumor antigen(s), increasing both transcription and adjuvanticity	Higher levels of transcription and immunogenicity	Less tested	54, 55
Cellular	Tumor cell	Tumor cells are expanded ex vivo and killed cells are injected with adjuvants. This does not require identifying individual neo-antigens	Does not require identification of tumor antigens, tumor cells can be engineered to express adjuvants or even co-stimulatory signals	Potential autoimmune side effects, low proportion of neoantigens	119–121
	Dendritic cell	Dendritic cells are professional antigen presenting cells primarily responsible for strong T cell responses; can be expanded and treated with tumor antigens and infused into patients.	Allows direct presentation to T cells with co-stimulatory signals.	Difficult and expensive manufacturing. HLA Diversity precludes an “off-the-shelf” product	122
Pathogen	Viral	Viral antigens can be encoded into viral vectors allowing efficient delivery to patients	More efficient delivery than nucleic acids	Immunity to vector complicates repeat vaccination	68
	Bacteria phages	Phages are well known to display antigens on their capsids which could be sources of antigen in a vaccine	Simple manufacturing (bacterial culture) contain some PAMPS	No replication in eukaryotic cells	NCT04034225
	Bacterial	Bacteria expressing tumor antigens can be killed and used as a vaccine	Bacteria encode numerous immune agonists, relatively simple manufacturing	Difficulty in precise control over antigen and adjuvant levels	70, 71, 123
in situ	Adjuvant only vaccine	Intratumoral injection of adjuvant stimulates intratumoral DCs and T cells	Does not require identification of tumor antigens, tumor cells can be engineered to express adjuvants or even co-stimulatory signals	Less likely to develop adaptive immune responses, Intratumoral environment is suboptimal site to stimulate T cell responses due to suppressive characteristics	83, 84
	Oncolytic Viruses	Viruses attenuated to replicate in cancer cells but not healthy cells could drive a systemic adaptive immune response against tumor antigens in addition to local immune effects	Agnostic to tumor type, augments both innate and adaptive immune responses, replicative capacity of virus increases immunogenicity	Typically requires intralesional delivery which is not possible in some cases	124
	Radiation	In rare circumstances, radiation can induce systemic responses through an abscopal effect	Radiation has well documented in-field tumorcidal effects independent of immunogenicity	Abscopal effect is rare and poorly understood	125, 126