Colorectal cancer (CRC) monoclonal antibody, double antibody and CAR-T therapy

Colorectal cancer (CRC) is the third most common cancer after lung cancer and the second most fatal cancer
.

At present, the 5-year overall survival rate of CRC is about 60%, and the 5-year overall survival rate of metastatic colorectal cancer (mCRC) has dropped to about 10%
.

In early diagnosed cases, surgery or combined chemotherapy and radiotherapy are still the preferred treatment options.
However, surgery is no longer effective for advanced CRC, and the efficacy of cytotoxic therapy may also fail due to the rapid evolution of drug resistance and cancer recurrence
.

Therefore, it is very necessary to develop other methods to treat CRC to improve its overall survival rate and reduce its severity
.

After decades of development, people have developed a series of drugs for CRC to improve patient compliance, reduce adverse events, and develop more personalized treatment strategies
.

Advances in chemotherapy and targeted drugs have increased the OS of mCRC patients to more than 40 months
.

Antibody therapy targeting tumor-associated antigens (TAA), angiogenesis pathways and immune checkpoints has higher selectivity and fewer side effects
.

At present, a variety of drugs have been approved for the treatment of CRC patients, and many drugs that interfere with other different pathways have also entered clinical trials (Figure 1)
.

This article gives a brief introduction to antibody-based CRC treatment therapies in recent years
.

Figure 1.
Monoclonal antibody targeted therapy for colorectal cancer (CRC).
Currently targeted therapy for epidermal growth factor receptor (EGFR) and vascular endothelial growth factor/receptor (VEGF/VEGFR) has been approved for use Treat patients with CRC (Figure 2)
.

Figure 2.
CRC Targeting Approved Drug 1.
1 Antibodies against the EGFR signaling pathway The EGFR family of drugs are transmembrane proteins involved in cell growth, differentiation and survival, including EGFR (HER1), HER2, HER3 and HER4
.

The binding of EGFR and its ligand (such as EGF) can induce homo/heterodimerization of EGFR, thereby triggering the phosphorylation of tyrosine kinase in the intracellular region of the receptor
.

Subsequently, complex signal networks activated by EGFR, such as the PI3K-Akt pathway and the Ras/RAF/MEK/MAPK pathway, play an important role in inhibiting cell processes such as apoptosis, tumor growth, metastasis, and angiogenesis (Figure 3)
.

Studies have shown that EGFR is highly expressed in CRC and can be used as a biomarker for the prognosis of metastatic CRC
.

For this reason, mAbs are designed to target EGFR to treat CRC
.

Figure 3.
EGFR-mediated signaling pathways and EGFR antibody treatment mechanism Cetuximab (cetuximab) Cetuximab is a chimeric monoclonal antibody with a molecular weight of approximately 152 kDa.
Compared with its natural ligand, cetuximab has a positive effect on EGFR Higher affinity, thereby inhibiting the tumorigenic effect of EGFR activation
.

Cetuximab combined with chemotherapy is the standard therapy for first-line treatment of patients with RAS wild-type metastatic CRC
.

A phase II trial study showed that cetuximab has moderate anti-tumor activity once a week intravenously, and it is well tolerated in patients with CRC who are refractory to chemotherapy
.

The large-scale study of Phase III clinical CRYSTAL established the status of the first-line application of cetuximab for CRC patients.
The study found that RAS wild-type patients can improve the overall survival of 8.
2 months through cetuximab treatment
.

Cetuximab was approved in China in 2006 under the trade name Erbitux
.

Panitumumab Panitumumab is a fully human mAb targeting EGFR.
It is approved to combine FOLFIRI and FOLFOX in the treatment of metastatic CRC in the first-line and second-line settings
.

The binding of Panitumab to EGFR leads to receptor internalization, induces apoptosis, inhibits cell growth, and reduces the production of VEGF and interleukin 8
.

The PRIME study showed that panitumumab combined with FOLFOX chemotherapy can prolong the median OS of KRAS wild-type mCRC patients by 4.
2 months compared with those with FOLFOX chemotherapy alone, and the median PFS by 1.
6 months
.

However, cetuximab and panitumumab are not beneficial to mCRC patients with RAS mutations, and suggest that the above-mentioned mutation status can predict the resistance of mCRC patients to EGFR mAb therapy
.

Therefore, the approved indications of cetuximab and panitumumab in mCRC are limited to KRAS/NRAS wild-type CRC patients
.

1.
2 Antibodies against (VEGF/VEGFR) signaling pathway The VEGF family, as an important factor in angiogenesis, is composed of six members: VEGF-A, B, C, D, E and placental growth factor (PlGF)
.

The VEGF protein family promotes angiogenesis through the tyrosine kinase receptors VEGFR-1 and VEGFR-2 (Figure 4)
.

During the growth of solid tumors, cells are deprived of oxygen and need new blood vessels to provide oxygen and nutrients to maintain survival
.

Studies have shown that the expression of VEGF is increased in several malignant tumors, including pancreatic cancer, liver cancer, gastric cancer and colorectal cancer
.

VEGF expression is positively correlated with CRC staging.
VEGF expression in stage IV patients is higher than that in stage II and III patients, and VEGF expression in dead patients is significantly higher than that in patients with 10-year survival
.

Figure 4.
The VEGF pathway and related inhibitors bevacizumab (bevacizumab) inhibit the biological activity of VEGF-A by preventing the binding of VEGF-A and VEGFR
.

The FDA approved bevacizumab combined with 5-fluorouracil-based chemotherapy as the first-line treatment for mCRC in 2004
.

Subsequently, many studies such as TREE, AVEX, MAX, TRIBE confirmed that bevacizumab combined with FOLFOX, XELOX (capecitabine + oxaliplatin), capecitabine, FOLFIRI, FOLFOXIRI (irinotecan +5 -Fluorouracil + leucovorin + oxaliplatin) and other chemotherapy regimens can prolong PFS in patients with mCRC, which further confirms the role of bevacizumab combined with 5-fluorouracil chemotherapy in the first-line treatment of mCRC
.

Aflibercept Aflibercept is a fully humanized recombinant fusion protein, which is formed by the fusion of the extracellular domains of VEGFR1 and VEGFR2 with the Fc part of human immunoglobulin, and is combined with VEGF-A, -B Combines with PlGF
.

Studies have shown that, compared with bevacizumab, aflibercept has a stronger anti-angiogenic effect, a longer half-life, a higher affinity for soluble VEGFs, and a higher affinity for PlGF
.

Multiple phase I trials have demonstrated the safety of aflibercept combined with chemotherapy in various cancers
.

In a multicenter phase III study, aflibercept combined with FOLFIRI regimen improved the survival and remission rate of CRC patients who had previously received oxaliplatin
.

Based on the above results, the FDA recommends that if mCRC patients are resistant to the first-line treatment with oxaliplatin or whose disease progresses after treatment, consider the second-line treatment with FOLFIRI combined with aflibercept
.

Ramucirumab Ramucirumab is a monoclonal antibody against VEGFR2, which can prevent the proliferation and migration of vascular endothelial cells by inhibiting the activation of VEGFR2 stimulated by ligand
.

According to two phase I clinical trials using Ramucirumab, the recommended dose of phase II monoclonal antibody is 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks
.

In the phase II study, intravenous Ramucirumab combined with mFOLFOX-6 prolonged PFS and OS, but some adverse reactions were observed, including neutropenia, neuropathy, and hypertension
.

The Phase III RAISE trial showed that compared with the second-line treatment of FOFIRI and placebo, the PSF of mCRC patients treated with ramucirumab combined with FOLFIRI was prolonged by 1.
2 months, and the OS was prolonged by 1.
6 months
.

Based on this result, the FDA approved ramolizumab combined with FOLFIRI regimen for the treatment of mCRC patients who are still progressing after treatment with a first-line regimen containing bevacizumab, oxaliplatin, and 5-fluorouracil
.

Immune checkpoint inhibitors Immune checkpoint blockers target inhibitory receptors or their ligands to rejuvenate exhausted T cells and change the field of immuno-oncology treatment (Figure 5)
.

The PD1 monoclonal antibodies pembrolizumab and nivolumab have been approved by the FDA for the treatment of CRC patients with high microsatellite instability (MSI-H) or mismatch repair (MMR) defects
.

Figure 5.
PD1/PDL1, CTLA-4 and other immune checkpoint signaling pathways and their role in the progression and metastasis of CRC.
Pembrolizumab Pembrolizumab is a humanized PD- 1 Monoclonal antibody, approved by the FDA in 2014 to prevent the interaction between PD-1 and PD-L1/2 to restore the immune response
.

The results of a phase Ib study conducted by O'Neil et al.
showed that 24% of CRC patients expressed PD-L1, and pembrolizumab treatment showed controllable safety
.

A phase II clinical trial showed that intravenous injection of 10 mg/kg pembrolizumab is more effective for patients with defective mismatch repair (dMMR) CRC compared with patients with CRC who are proficient in mismatch repair
.

In another study, Dung et al.
reported that pembrolizumab administered every 3 weeks to CRC patients with dMMR/MSI-H can provide long-lasting anti-tumor activity and acceptable safety
.

In May 2017, the FDA approved Pembrolizumab to treat patients with CRC solid tumors with MSI-H/dMMR
.

Nivolumab Nivolumab is a fully human mAb with a molecular weight of 146 kDa.
It also targets PD-1 to block its interaction with PD-L1 and PD-L2 , Thereby avoiding the inhibition of PD-1 mediated anti-tumor response
.

According to the phase I clinical trial of Yamamoto et al
.

In patients with solid tumors, the safety of nivolumab is acceptable below 20 mg/kg
.

In the CheckMate-142 study, nivolumab monotherapy for dMMR/MSI-H mCRC achieved an objective response rate of 31%, which is similar to the objective response rate of pembrolizumab monotherapy
.

In August 2017, the efficacy of nivolumab in the field of CRC was recognized by the FDA and was approved for use in adults with metastatic CRC or MSI-H or dMMR who have progressed after treatment with fluorouracil, oxaliplatin and irinotecan.
Treatment of pediatric patients (≥12 years old)
.

How to further improve the efficacy of these immunotherapy advantageous populations? Overman of MD Anderson Cancer Center in the United States conducted a multi-center phase II trial with nivolumab monotherapy and the combination of nivolumab and ipilimumab in the treatment of patients with metastatic dMMR/MCI-H CRC, and the results showed that the combined regimen improved The treatment effect, including 12 weeks or longer disease control rate (80%), ORR (55%) and 12 months OS (85%), and proved that treatment-related adverse reactions in CRC patients are controllable Of
.

In July 2018, the FDA approved ipilimumab combined with nivolumab for MSI-H/dMMR previously treated metastatic CRC
.

Bispecific antibodies Bispecific antibodies are a new concept in immunotherapy, in which an antibody is designed to have binding sites for two different targets
.

Currently, no bispecific antibody against CRC has been approved
.

However, many preclinical and clinical studies are evaluating the therapeutic effects of bispecific antibodies on CRC (Figure 6)
.

Figure 6.
Bispecific antibody is a representative therapeutic drug for CRC.
Many clinical trials are also studying the combination of radiotherapy and immunotherapy
.

Radiation can cause DNA damage, thereby producing a large number of new mutations and new antigens, these new mutations and new antigens will be activated by T cells
.

Therefore, the combination of radiotherapy and immunotherapy seems to be an interesting research direction, and many clinical studies are moving in this direction
.

CAR-T therapy CAR-T cell therapy is becoming a potential candidate for cancer treatment
.

Although most of the early CAR-T cell therapy research mainly focused on the treatment of hematological malignancies, it has also been successful
.

However, in clinical trials, there is an increasing demand for CAR-T in the treatment of solid tumors
.

At present, CAR-T therapies for different TAA treatments for CRC have undergone clinical trials, including CEA, EGFR, MSLN, MUC1, NKG2D and its ligands, HER2, c-MET and CD133, etc.
(Figure 7).
We look forward to follow-up clinical progress.

.

Figure 7.
Summary of CAR-T clinical trials for the treatment of CRC CRC is a highly complex molecular heterogeneous disease, with frequent mutations to conventional treatments that lead to drug resistance
.

Although recent progress has been made in determining CRC treatment targets, the needs in CRC treatment are far from being met
.

Cetuximab treatment shows that antibody resistance is one of the main obstacles to the treatment of CRC patients.
It is only effective for CRC patients with wild-type EGFR and KRAS expression, which highlights the importance of basic research in understanding the progress and metastasis of CRC
.

Therefore, in order to improve the clinical outcome of CRC patients, it is still important to understand the pathological mechanism of CRC and the identification of new therapeutic targets for the development of new antibody therapies for effective CRC treatment
.

Based on more and more recent studies, the therapeutic potential of bispecific antibodies and CAR-T therapy in CRC has also been verified
.

In order to obtain more clinical benefits in the future, the combination of drugs may become a trend
.

References 1.
Comprehensive review of targeted therapy for colorectal cancer.
2.
Antibody-based therapy in colorectal cancer.
3.
Current advancements and future perspectives of immunotherapy in colorectal cancer research.
4.
Recent advances in monoclonal antibody therapy for colorectal cancers.
5 .
Monoclonal antibodies and chimeric antigen receptor (CAR) T cells in the treatment of colorectal cancer.
6.
Mechanisms of resistance to anti-EGFR therapy in colorectal cancer.
7.
Emerging VEGF-receptor inhibitors for colorectal cancer.
8.
Development and clinical application of bispecific antibody in the treatment of colorectal cancer.
9.
Chimeric antigen receptor T-cell therapy for colorectal cancer.
10.
Bispecific antibodies in colorectal cancer therapy: recent insights and emerging concepts.