Immunotherapy plays an important role in controlling tumors. Combined immunotherapy is based on the use of more than one immunotherapy. It can intervene andregulate multiple processes of immune response through, chemoradiotherapy [30–32] and targeted therapy[33, 34] by promoting anti-tumor immune response reduce the risk of drug resistance. The combination of immunotherapies is one of the most promising approaches being studied. In particular, the combination of anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) has shown positive results in tumor treatment and significant enhancement in patients with metastatic melanoma, advanced RCC, and metastatic CRC [16, 38]. Cope et al. reported that recurrent SCLC showed better response to nivolumab-ipilimumab compared to the current chemotherapy, interpreted as long-term survival benefits. Ready et al. reported that a combination of nivolumab and low-dose ipilimumab was effective and tolerable as a first-line treatment of advanced/metastatic non-small cell lung cancer (NSCLC). Based on conditional survival analysis of first-line treatment, Shao showed that patients with advanced RCC put on nivolumab plus ipilimumab therapy had high survival rate compared with sunitinib.
Recently, the combination therapy of ipilimumab and anti- PD-1 antibody showed promising clinical benefit in some malignant tumors, advanced melanoma, RCC and other tumors . Combination therapy and ipilimumab or nivolumab monotherapy showed improved ORR, CR and PR [37, 41, 45, 46]. The present systematic review showed that the combination of nivolumab and ipilimumab had significantly high CR, PR and ORR compared with ipilimumab monotherapy. Complete response with nivolumab-ipilimumab therapy was 4.89 times higher than ipilimumab monotherapt, while the PR and ORR were 2.75 and 3.31 times than ipilimumab monotherapy, respectively. These findings show that the combination therapy was more effective than ipilimumab monotherapy. Elsewhere, Postow et al reported that nivolumab-ipilimumab combination therapy had a higher ORR and progression-free survival rate compared with ipilimumab monotherapy, in treatment-naive patients with advanced melanoma. Increased response rate and improved progression-free survival was reported in ipilimumab-nivolumab combination when compared with ipilimumab alone in a randomized phase III trial in treatment-naive patients with metastatic melanoma.
Nivolumab is a class of ICIs that PD-1 receptors that activate downstream signaling pathways by inducing FoxP3 expression and promoting Treg (iTreg) cell differentiation. The incidence of CR and PR and ORR in individuals on nivolumab-ipilimumab combination therapy was 1.13, 1.50 and 1.40 times respectively, as high than those on nivolumab monotherapy. These findings emphasize the effectiveness of the combination therapy. Antonia et al. reported that nivolumab-ipilimumab combination therapy had a higher prolonged anti-tumour activity in previously treated patients than nivolumab monotherapy. Preliminary data on metastatic RCC, suggests that combination therapy had a higher ORR than nivolumab monotherapy in a different trials[20, 49]. Morse  reported that a combination therapy (nivolumab with low-dose ipilimumab) had numerically higher response rates and improved long-term clinical benefit relative to anti-programmed death-1 monotherapy. Principaly CTLA-4 binds B7 ligands (B7-1/CD80 and B7-2/CD86) on antigen presenting cells that compete with the CD28 receptor. The CTLA-4 protein and its B7 ligand are mainly expressed on immune cells, suggesting that CTLA-4 pathway plays a major role in lymph nodes. PD-L1, the PD-1 ligand, is widely expressed, mainly on regulatory peripheral T cells . Although CTLA-4 and PD-1 antibodies are both checkpoint inhibitors, their action mechanisms are neither the same nor complementary. Therefore, higher anti-tumor activity was seen with a combination therapy than ipilimulab or nivolumab.
Based on our analysis, we can conclude that the combination of nivolumab and ipilimumab is more effective than nivolumab alone, consistent with previous findings [18, 19]. In contrast, Kreft  showed that there was no difference in action and outcome between nivolumab monotherapy and ipilimumab-nivolumab combination therapy in patients with melanoma. Elsewhere, checkpoint monotherapy inhibitors targeting PD-1 and PD-L1 were not effective in metastatic colorectal cancer patients with microsatellite stable tumors.
Many combination immunotherapies have been developed, nivolumab-ipilimumab being the most common. There are two dosages of this combination; nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (N1I3) and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (N3I1), however no studies have been done to determine their differential effectiveness, if any. This possibility should be evaluated.. Although there was no significant difference between N1I3 and N3I1 in CR, N1I3 yielded better results in PR and ORR than N3I1, suggesting that the efficacy of N1I3 may be better than that of N3I1. Sharma et al.  reported that with longer follow-up, N1I3 showed sustained antitumor activity than N3I1. Glutsch on his part investigated the presence and extend of side effects in advanced melanoma cases on ipilimumab-nivolumab combined immunotherapy. Here, renal toxicity was tolerable, and three doses of nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) showed deep partial relief on chest and abdominal CT scans. This result not only support our findings on N1I3, but emphasized on the potential benefit of combination imunotherapies in tumor.
We also analyzed all common adverse reactions of every grade. Adverse reactions of grade 3 or higher in group combination were elevated than those in monotherapies. Nivolumab-ipilimumab increased response rate with more side effects than ipilimumab monotherapy. Kreft  reported that combined ipilimumab and nivolumab was associated with a higher TRAEs compared with the monotherapy, but N1I3 induced elevated grade 3 or higher TRAEs than N3I1, consistent with Antonia et al.. When comparing treatment groups, common grade 3 or 4 TRAEs in the nivolumab-ipilimumab group arose early but resolved within the first 4–6 months of treatment . In contrast, both early and chronic toxicity were apparent in the sunitinib group, despite dose adjustments. Most selected treatment-related adverse events occurring within 30 days of the last dose in the nivolumab-ipilimumab group were low-grade, and the majority resolved and were manageable using established algorithms. Health-related quality life was maintained or significantly improved from baseline analysis of patients under nivolumab-ipilimumab compared those on sunitinib alone, further supporting the preference of the combination therapy.
The main TRAEs associated with nivolumab use include increased ALT and AST, pruritus, diarrhoea, fatigue, nausea, hypothyroidism, decreased appetite, vomiting, and rash. After extensive systematic review, Bajwa et al. found that the most common adverse effects encountered were colitis (14/139), hepatitis (11/139), adrenocorticotropic hormone insufficiency (12/139), hypothyroidism (7/139), type 1 diabetes (22/139), acute kidney injury (16/139) and myocarditis (10/139). The most common treatment approach was the cessation of the immune checkpoint inhibitor, initiation of steroids and supportive therapy[58, 59]. Motzer et al. reported that among all patients treated, the most common TRAEs in the grade 3–4 nivolumab and ipilimumab groups were elevated lipase (57 of 547 [10%]), elevated amylase (31 [6%]) and elevated ALT (28 [5%]). Reporting of corticosteroid use for ICIs has been effective among various studies.
There is an increasing number of immunotherapy and molecular targeting agents being evaluated in monotherapies as well as in various combinations, but the choice of right therapy, sequence and dosage of candidate agents and immunotherapies and treatment for patients that progress on immune checkpoint inhibitors remains a challenge