Table 1.

Advantages and limitations of immunotherapies and their combinations.

Immunotherapy	Combination	Successes/Advantages	Limitations	References
Checkpoint Inhibitors	Checkpoint Inhibitors	Significantly improved response rates Long term disease eradication	High cost of treatment Dose limitation and increased grade treatment-related adverse events (TRAEs) Development of resistance Tumors lacking immune infiltrates may not respond Incomplete understanding of the determinants of hyperprogression	[11,29,52,53,54,55,56,57,58,59,65,66,67,68,69,70]
	Chemotherapy	Significantly improved response rates Increase in release of tumor-associated antigens and effector cells’ activation Some chemotherapies increase expression of checkpoint molecules, which can be overcome by combination with checkpoint inhibitors	Dose and sequence of combination is not universal Chemotherapy may inhibit activity of immune effectors Increased TRAEs	[30,31,32,33,35,36,50,64]
	Radiotherapy	Significantly improved response rates May help overcome resistance to checkpoint inhibition as monotherapy Radiotherapy leads to increased tumor antigen release, T cell activation/infiltration, and major histocompatibility complex (MHC) class I expression Increased abscopal effects	Dose-limiting toxicities prevalent Type of radiation, fractionation, and sequence of combination is not universal Variable results with combination in neoadjuvant, concurrent, and adjuvant settings Radiation may have direct negative effects on immune effectors and may increase frequency of Tregs	[71,72,73,74,75,76,77,78,79]
Cancer Vaccines	Checkpoint Inhibitors	Improved response rates Vaccine induces anti-tumor immune effectors which can be acted upon by checkpoint inhibitors to improve immune responses	Most antigens that are the target of cancer vaccines are not tumor-restricted antigens; hence there is a risk of off-target effects Resistance through antigen escape and upregulation of additional checkpoint molecules is possible Not all studies have found added benefit of the combination, which highlights the need to design potent cancer vaccines No optimal dosing and sequence of treatments have been identified Unclear if the combination is efficacious in adjuvant or neo-adjuvant setting	[48,80,81,82,83]
Co-stimulatory Molecule Agonists	Checkpoint Inhibitors	Promote activation, and development and maintenance of T cell memory Multiple preclinical studies show improved activation of immune responses and anti-tumor effects of the combination	Existing trials of monotherapies show high toxicity or low efficacy Lack of available clinical trials results of combinations Unclear mechanisms for monotherapy or combinations Timing of treatment for optimal efficacy is unclear	[84,85,86,87,88,89,90]
Tumor Infiltrating Lymphocyte (TIL) and Chimeric Antigen Receptor (CAR) T Cell Therapy	Checkpoint Inhibitors, Chemotherapy	Unprecedented response rates, including high frequency of complete responses High response rates even in patients who have failed multiple prior therapies Two CD19 CAR T cells are already U.S. Food and Drug Administration (FDA)-approved Amenable to modulation of T cell function to improve efficacy, decrease off-target effects, and decrease toxicity CAR T cell therapy is not MHC-restricted Combination helps overcome exhaustion	Significant risk of off target effects and toxicities Neurotoxicity and cytokine release syndromes are challenges that still needs to be overcome Lengthy and stringent manufacturing process Lack of sufficient trials evaluating the feasibility, dosing sequence, and toxicities associated with the combinations Treatment is expensive In vivo persistence of infused cells are not optimal	[91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117]