Systemic adverse effects and toxicities associated with immunotherapy: A review

Table 1 Immunotherapy agents approved for treatment by the United States Food and Drug Administration in various types of cancers

Organ system	Cancer	Tumor marker	Staging at initiation of immunotherapy	Immunotherapy
Brain and central nervous system	GBM	IDH mutations, 1p19q deletion, MGMT promoter methylation, EGFRVIII amplification	Recurrent GBM	Bevacizumab
	Pediatric neuroblastoma	Homovanillic acid, Vanillylmandelic acid, LDH, NSE	High risk patients with partial response to first line agents	Dinutuximab
Head and neck	Head and neck SCC	CEA, SSC-Ag	Recurrent/metastatic SSC which progressed during/after platinum-based chemotherapy	Pembrolizumab
Breast	Breast cancer	BRCA1, BRCA2, CA 15-3, CA27.29, ER positive, PR positive, HER2/neu	HER2/neu positive	Trastuzumab
			Unresectable locally advanced or metastatic triple-negative, PD-L1-positive breast cancer	Atezolizumab
Gastrointestinal	SCC of the Esophagus	CEA, CA 19-9, SSC-Ag	Locally advanced or metastatic SSC, that progressed after treatment with one or more lines of standard therapy	Pembrolizumab
	Gastric and gastroesophageal junction cancer	CEA, CA 19-9, CA 72-4, DPD	Advanced cancer, that progressed despite two or more lines of standard treatment	Pembrolizumab
	Gastric cancer	CEA, CA 19-9, CA 72-4, DPD	Advanced cancer	Nivolumab (only approved in Japan)
	Pancreatic cancer	CA 19-9, DPD, CEA: Not frequently used	Advanced cancer with high microsatellite instability or high tumor mutational burden	Pembrolizumab
	Colorectal cancer	CEA, KRAS, BRAF V600, CA 19-9: Not frequently used, DPD, MSU, dMMR	Progressive CRC after Fluoropyrimidine Oxaliplatin and irinotecan treatment regimen	Pembrolizumab
Hematological	CLL	Beta-2-microglobulin, chromosome 17p deletion	Relapsed CLL, in combination with Fludrabine and cyclophosphamide	Ofatumumab
			Combination with Chlorambucil	Obinutuzumab
	B-cell precursor ALL	BCR-ABL	Relapsed/refractory Ph-negative B-cell Precursor ALL	Blinatumomab
	Follicular lymphoma	Beta-2-microglobulin	Relapse/refractory	Obinutuzumab
	Hodgkin’s lymphoma	CD20	Non-responsive to therapy or relapse after > 3 therapies	Pembrolizumab
	Non-Hodgkin’s lymphoma	CD20	Relapsed/progressing after autologous Hematopoietic stem cell transfer + Brentuximab Vedotrin or after 3 systemic therapies	Nivolumab
	Multiple myeloma	Beta-2-microglobulin, immunoglobulins	(1) Initial treatment in combination with dexamethasone, in patients eligible for autologous HSCT and maintenance therapy after autologous HSCT; (2) After > 3 therapies or non-responsive to proteasome inhibitor and immunomodulatory drug; (3) Combination with lenalidomide + dexamethasone or bortezomib + dexamethasone after > 1 therapy; And (4) Combination with revlimid + dexamethasone after 1-3 therapies	(1) Linalidomide; (2) Daratumab; (3) Daratumab; And (4) Elotuzumab
Respiratory	NSCLC	ALK gene, BRAF V600, KRAS, PD-L1, ROS1	Metastatic cancer expressing PD-L1 and progressing during/after platinum-based chemotherapy or with EGFR or ALK mutations	Pembrolizumab
			In combination with pemetrexed and carboplatin, with or without PD-L1 expression	Pembrolizumab
			Progressing during/after platinum-based chemotherapy	Nivolumab
			Progressing cancer while using approved therapy for the mutation in metastatic cancer expressing PD-L1 and progressing during/after platinum-based chemotherapy or with EGFR or ALK mutations	Atezolizumab
	Squamous NSCLC		First line in combination with gemcitabine + cisplatin	Necitumumab
Renal	Renal cell carcinoma		Advanced RCC after antiangiogenic therapy	Nivolumab
Skin	Melanoma	BRAF V600	Unresectable cutaneous, subcutaneous or nodular lesions in relapsing melanoma after surgical resection	Talimogene Iaherparepvec (vaccine)
			Unresectable/metastatic	Pembrolizumab
			Unresectable/metastatic without BRAFV600 mutation	Nivolumab, Ipilimumab
			Adjuvant therapy for stage III	Ipilimumab
Urinary	Bladder cancer	Bladder tumor antigen, chromosome 3, 7, 17, 9p21 mutation, FGFR2, FGFR3 mutation	Locally advanced or metastatic bladder cancer, progressed during/after platinum-based chemotherapy or within 12 mo neoadjuvant/adjuvant treatment	Avelumab, Durvalumab, Pembrolizumab, Nivolumab, Atezolizumab
			Locally advanced or metastatic cancer with patient ineligible for platinum-based chemotherapy	Pembrolizumab, Atezolizumab

GBM: Glioblastoma multiforme; SCC: Squamous cell carcinoma; SSC-Ag: Squamous cell carcinoma antigen; CLL: Chronic lymphocytic leukemia; ALL: Acute lymphoblastic leukemia; HSCT: Hematopoietic stem cell transfer; NSCLC: Non small-cell lung carcinoma.

Table 2 Overview of some of the common immunotherapeutic agents and their proposed mechanisms

Agent	Mechanism of action
Ipilimumab	CTLA-4 inhibitor
Nivolumab	PD-1 inhibitor
Pembrolizumab	PD-1 inhibitor
Atezolizumab	PD-L1 inhibitor
Avelumab	PD-L1 inhibitor
Durvalumab	PD-L1 inhibitor
Talimogene Iaherparepvec	Cancer vaccine (directly destroys cancer cells, upregulates production of GM-CSF)
Necitumumab	EGFR inhibitor
Bevacizumab	VEGF inhibitor
Elotuzumab (anti-SLAMF7 monoclonal antibody)	Anti-SLAMF7 monoclonal antibody
Daratumumab (anti-CD38 monoclonal antibody)	Anti-CD38 monoclonal antibody
Lenalidomide	Immunomodulatory agent
Obinutuzumab	CD20 inhibitor
Ofatumumab	CD20 inhibitor
Blinatumomab	Bispecific T-cell engager
Trastuzumab	HER2/neu inhibitor
Dinutuximab	GD2-binding monoclonal antibody

CTLA-4: Cytotoxic T-lymphocyte associated protein 4; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1.