Take a look at the Recent articles

Immunotherapy and colon cancer

Timothy Allen

Global Allied Pharmaceutical, Center for Excellence in Research & Development, USA

Abdullateef Al-Hadeethi

Global Allied Pharmaceuticals, Amman , Jordan

E-mail : dr.abdulateef@gmail.com

DOI: 10.15761/ICST.1000180.

Article
Article Info
Author Info
Figures & Data

Abstract

Colon cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the U.S. The exact cause of the colonic cancer is still unknown but has several risk factors like the age, the colonic polyps, the genetic alterations and others. The aim of this review is to put a light on the pathophysiology of the colonic cancer like the genomic and chromosomal instabilities and oncogens mutations like the EGFR ; and focus on the immunotherapies available for treating it including the FDA approved agents like Cetuximab, Bevacizumab, Regorafenib , and other drugs that are still under clinical trial.

Key words

colon cancer , polyps , EGFR , cetuximab

Abbreviations

HNPCC: Hereditary Non Polyposis Colon Cancer, FAP: Familial Adenomatous Polyposis, APC: Antigen Presenting Cells, CIN: Chromosomal Instability, MMR: Mismatch Repair, CRC: Colorectal Cancer, mCRC: metastatic Colorectal Cancer, CIMP: CpG Island Methylator Phenotype, TGFB: Transforming Growth Factor B, EGFR: Epidermal Growth Factor Receptor, MAPK: Mitogen Associated Protein Kinase, PI3K: Phosphatidylinositol 3-Kinase,  VEGF: Vascular Endothelial Growth Factor,  MAb: Monoclonal Antibody, CTL: Cytotoxic T-Lymphocyte,  PD-1: Programmed Death 1,  HFSR: Hand Foot Skin Reaction,  TK: Tyrosine Kinase,  RTK: Receptor of Tyrosine Kinase,  FGFR: Fibroblast Growth Factor Receptor,  PDGFR: Platelet derived Growth Factor receptor,  JAK-2: Janus Kinase 2,  ERK: Extracellular Signal regulated Kinase,  TNF: Tumor Necrosis Factor, TRAIL: TNF Related Apoptosis Including Ligand,  rhGM-CSF: recombinant human Granulocyte Macrophage Colony Stimulating Factor,  bi-shRNA: bifunctional short hairpin RNA,  AD5: Adenoviral Serotype 5, hGCC: human Granulocyte Cyclase C,  mTOR : Mammalian Target of Rapamycin,  CIK: Cytokine Induced Killer

Introduction

Colon cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death in both men and women in the US [1]. The American Cancer Society estimated 96,830 new cases of colon cancer in the United States in the year 2014 . Additionally, in the same year 50,310 cases of death due to colon cancerhave been reported [2]. The incidence of colorectal cancer is equal for both men and women. The American Cancer Society estimated that colon cancer was diagnosed in 48,450 men and 48,380 women in the United States in the year 2014 [3].

Although, the incidence of colon cancer varies widely from country to country throughout the world, colon cancer is a common disease in the United States. Recent data on colon cancer in the United States showed that incidence and death due to this cancer isdisproportionately higher in African Americans than in whites. Hispanics have the lowest incidence and mortality from colorectal cancer.

The exact cause of colon cancer is still not known. Several risk factors have been found that increases the risk of developing colon cancer. More than 90% of people with colon cancer are diagnosed after the age of 50 and the average age of diagnosis is 72. Generally, polyps grow on the inner wall of colon or rectum. They are more common in people over age 50. Risk of colon cancer increases due to the changes in certain genes [4].

Hereditary nonpolyposis colon cancer (HNPCC) is a type of inherited colon cancer and accounts for about 2 % of all colon cancer. Most people with an altered HNPCC gene develop colon cancer, however, it is not just limited to colon cancer, and other organs such as female reproductive organs but also other parts of the gastrointestinal tract,might be affected by malignant transformation. Familial adenomatous polyposis (FAP) is caused by a change in a specific gene called APC. FAP accounts for less than 1% of all colon cancer [4].

A person having colon cancer may develop colon cancer a second time. Women with a history of ovary, uterus or breast cancer are at a higher risk  of developing colon cancer. Patients with long term (10 years or more) history of inflammatory bowel disease, either in the form of ulcerative colitis or Crohn’s disease, are susceptible to colon cancer. Diets high in red meat and fat and low in calcium, folate, and fiber increases the risk of colon cancer. Some studies also suggest that a diet low in fruits and vegetables increases the risk of colon cancer. A person who smokes cigarettes may be at increased risk of developing polyps and colon cancer [4].

Pathophysiology and molecular basis

Colon cancer is a disease caused by disrupted growth control. There is an early genetic alteration which takes place in the colonic epithelial cells lining of the bowel wall.

Genomic instability

Loss of genomic stability increases the acquisition of multiple mutations which leads to the development of colon cancer [5]. It includes chromosomal instability (CIN), microsatellite instability, aberrant DNA methylation and DNA repair defects [5,6].

Chromosomal instability

It is found in up to 85% of CRCs [6]. Loss of function of tumour suppressor genes, including APC, whose normal function is to oppose tumorigenesis, has been implicated in the development of chromosomal instability [7]. Loss of function of the APC gene is further associated with familial adenomatous polyposis (FAP), in which hundreds to thousands of adenomatous colonic polyps develop, leading to almost 100% lifetime risk of developing colon cancer [8,9].

Microsatellite instability

It involves inactivation of genes responsible for DNA mismatch repair (MMR) through somatic mutation or aberrant methylation [6]. This loss of MMR gene function, leads to inability of repairing strand slippage within nucleotide repeats and changes the size of microsatellites [5].

Germline mutations of MMR genes are responsible for Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), which carries a lifetime risk of CRC of about 80% [5,9]. Mutations leading to loss of function have been identified in four genes involved in MMR: MLH1, MSH2 (accounting for the majority of cases), MSH6 and PMS2. Lynch syndrome is the most common hereditary CRC syndrome accounting for 2%–3% of all cases [8,10].

Aberrant DNA methylation

Aberrant methylation of DNA in colon cancer causes loss in the MMR functioning [5,11]. In the CRC genome, there is aberrant methylation within promoter associated CpG islands, leading to silencing of gene expression [5,12]. Hypermethylation of promoters containing CpG islands is known as the CpG island methylator phenotype (CIMP) [6]. This phenomenon is observed in about 15% of CRCs, most of which shows loss of MLH1 expression resulting in MMR deficiency and microsatellite instability [5,13].

DNA base excision repair genes

The MYH gene is a base excision repair gene, responsible for repairing DNA damaged by reactive oxygen species [8,14]. Polyposis develops in the presence of germline mutation of both MYH alleles [5]. The mechanism of disease following germline inactivation of MYH is via subsequent somatic mutation of the APC gene, causing chromosomal instability [15].

Tumor suppressor genes

TP53 is a key tumor suppressor gene that is mutated in about half of all colorectal cancers [6]. Inactivation of the TP53 gene often coincides with malignant transformation of adenomas [5,6].

Transforming growth factor β (TGFβ) signaling is an important tumor suppressor pathway. Deregulation of this pathway is a frequent observation in colorectal cancers, mediated by inactivating mutations of receptor genes (TGFBR1, TGFBR2) or post receptor signaling pathway genes (SMAD2, SMAD4) [6]. A number of germline mutations, ultimately leading to downregulation of TGFβ signaling, have been reported, including inactivating mutations of SMAD4 [8].

Oncogenes

The pathways which exhibit oncogenic mutations in colorectal cancers, include the epidermal growth factor receptor (EGFR), mitogen-associated protein kinase (MAPK) pathway and the phosphatidylinositol 3-kinase (PI3 K) pathway [5,6,16].

EGFR activation triggers an intracellular phosphorylation cascade through downstream effectors RAS and BRAF, amplified through the MAPK pathway to promote cell growth [6]. RAS and BRAF are implicated as oncogenes in a number of human cancers. Activating mutations promoting CRC have been identified in both genes [16]. Mutations in KRAS are found in about 40% of CRCs, occurring as a relatively early event in the adenoma-carcinoma sequence [6,17].

Mutations of the PIK3CA gene, leading to the upregulation of PI3 K signaling, are present in approximately 15%–20% of CRCs. Resulting enhanced prostaglandin E2 synthesis inhibits apoptosis of CRC cells [18].

Immunotherapy

Current immunotherapy for colon cancer fall into following categories: monoclonal antibodies, kinase inhibitors, vaccine therapy and adoptive cell therapy.

Monoclonal antibodies

Colon cancer is one of the GI cancers with existing FDA-approved immunotherapeutic monoclonal antibodies. These include: Cetuximab, which directly inhibits the epidermal growth factor receptor (EGFR), Bevacizumab, which inhibits angiogenesis by directly targeting the vascular endothelial growth factor (VEGF) protein and Panitumumab, which is another EGFR inhibitor.

1. Cetuximab: It is a recombinant, human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor (EGFR). Cetuximab is composed of the Fv regions of a murine anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions and has an approximate molecular weight of 152 kDa. Cetuximab is produced in mammalian (murine myeloma) cell culture [19].

Cetuximab has been approved by FDA as a treatment for EGFR-expressing colon cancer in combination with irinotecan in patients whose disease is refractory to irinotecan-based chemotherapy and as monotherapy for patients with EGFR-expressing colon cancer after failure of both irinotecan and oxaliplatin-based chemotherapy regimens. It is also approved as the first line treatment for in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) in patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use.
When used intravenously, clearance is 0.08 to 0.02 L/h/m2; half-life is 112 hours (range 63–230 hours).It is not indicated in patients with k-ras mutation positive colorectal cancer.

Warnings are serious infusion reactions and cardiopulmonary arrest.The most common adverse events associated with Cetuximab are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection. The most serious adverse reactions with Cetuximab are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

2. Bevacizumab: A recombinant humanized monoclonal antibody directed against the vascular endothelial growth factor (VEGF), a pro-angiogenic cytokine. Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels. It has been approved by FDA as first-line therapy for metastatic colorectal cancer  in combination with FOLFIRI (5-fluorouracil, leucovorin, irinotecan) or fluropyrimidine–oxaliplatin-based chemotherapy, as well as second line treatment of patients with metastatic colorectal cancer (mCRC) whose disease has progressed (i.e., the cancer continues to grow or spread) while on first-line treatment with a non bevacizumab-containing regimen [20].

Warnings are gastrointestinal perforations, surgery and wound healing complications, and hemorrhage. Most common adverse events associated with bevacizumab are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

3. Panitumumab: Recombinant human IgG2 kappa monoclonal antibody that binds specifically to the human Epidermal Growth Factor Receptor (EGFR). Overexpression of EGFR is detected in many human cancers, including those of the colon and rectum. When Panitumumab binds to EGFR, it competitively inhibits the binding of ligands for EGFR. This result in inhibition of cell growth, induction of apoptosis, decreased pro-inflammatory cytokine and vascular growth factor production [21].

It has been approved by FDA for the treatment of patients with wild-type KRAS (exon 2 in codons 12 or 13) metastatic colorectal cancer (mCRC) as determined by an FDA-approved test for this use:

  • As first-line therapy in combination with FOLFOX
  • As monotherapy following disease progression after prior treatment with fluropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy

Most common adverse events associated with Panitumumab are skin rash with variable presentations, paronychia, fatigue, nausea, and diarrhea.

4. Ramucirumab: It is a recombinant human IgG1 monoclonal antibody that specifically binds to vascular endothelial growth factor receptor  2 (VEGF), and blocks binding of VEGFR ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand stimulated activation of VEGF Receptor 2, thereby inhibiting ligand-induced proliferation, and migration of human endothelial cells. a pro-angiogenic cytokine. It has been approved by FDA for use in combination with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) for the treatment of metastatic colorectal cancer in patients whose disease has progressed during or after therapy with bevacizumab. Based on a population PK analysis, the mean (% coefficient of variation [CV%]) volume of distribution at steady state for ramucirumab was 5.5 L (14%), the mean clearance was 0.014 L/hour (30%), and the mean elimination half-life was 15 days (24%).Warnings are gastrointestinal perforations, Hemorrhage, arterial thromboembolic events, Hypertension,  surgery and wound healing complications, and Reversible Posterior Leukoencephalopathy Syndrome The most common adverse reactions observed are hypertension, diarrhea, headache, Hyponatremia, anemia and intestinal obstruction [22].

Other MABs that are in various stages of clinical trials are listed in Table 1.

Table 1.Non-FDA approved monoclonal antibodies [23-25]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Edrecolomab

NCT00002968

Phase III

Randomized, Safety/Efficacy study, open label

EpCAM

Nimotuzumab

NCT00972465

Phase II

Non Randomized, Safety study, open label

EGFR

Sym004

NCT02083653

Phase II

Randomized, Safety/Efficacy study, open label

EGFR

B. Checkpoint inhibitors

There are no checkpoint inhibitors that are currently approved for FDA. However, the few drugs that are in Clinical trials Phase I-III are listed in Table 2.

Table 2.Non-FDA approved checkpoint inhibitors [26-29]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Varlilumab

NCT02335918

Phase I, Phase II

Safety/Efficacy study, open label

CD27

 Pembrolizumab

NCT02260440

Phase II

Safety/Efficacy study, open label

PD-1

Nivolumab

NCT02060188

Phase I, Phase II

Non Randomized, Efficacy study, open label

PD-1

MEDI4736

NCT02227667

Phase II

Safety/Efficacy study, open label

B7H1

C. Kinase inhibitors

1. Regorafenib: Regorafenib and its active metabolites inhibit multiple membrane-bound and intracellular kinases, that are involved in normal cellular functions and pathologic processes, including those in the RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAF V600E, SAPK2, PTK5, and Abl pathways [30].

Regorafenib has received FDA approval for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, with an anti-VEGF therapy, and, if KRAS wild type, with an anti-EGFR therapy. The coefficient of variation of AUC and Cmax is between 35% and 44%, highly bound (99.5%) to human plasma proteins, metabolized by CYP3A4 and UGT1A9 and elimination half life is 28 hours (14 to 58 hours).

The most common adverse events associated with Regorafenib are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, and infection, decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea. The most serious adverse drug reactions in patients receiving Regorafenib are hepatotoxicity, hemorrhage, and gastrointestinal perforation.

Other Kinase inhibitors that are in various stages of clinical trials are listed in Table 3. 

Table 3.Non-FDA approved kinase inhibitors [31-41]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Vemurafenib

NCT02164916

Phase II

Randomized, efficacy study, open label

BRAF (V600E) kinase

Imatinib

NCT00041340

Phase II

Safety/Efficacy study, open label

TK

Erlotinib  hydrochloride

NCT00032110

Phase II

Safety/Efficacy study, open label

EGFR

Fruquintinib

NCT02314819

Phase III

Randomized, Efficacy study, Double blind

VEGFRs 1, 2, and 3

Famitinib

NCT01762293

Phase II

Randomized, Safety/Efficacy study, double blind

RTK

BIBF 1120

NCT02149108

Phase III

Randomized, Safety/Efficacy study, double blind

VEGFR, FGFR, PDGFR

 Pacritinib

NCT02277093

Phase II

Safety/Efficacy study, open label

JAK2, JAK2V617F

Anlotinib

NCT02332499

Phase II, Phase III

Randomized, Safety/Efficacy study, double blind

RTK

Ruxolitinib

NCT02119676

Phase II

Randomized, double blind

JAK 1 and 2

MK2206

NCT01802320

Phase II

Efficacy study, open label

Proteinkinase B

ONC201

NCT02038699

Phase I, Phase II

Safety/Efficacy study, open label

Akt/ERK

D. Vaccine therapy

Tumor antigens that have been targeted in colon cancer include carcinoembryonic antigen (CEA), MUC1, guanylyl cyclase C, and NY-ESO-1. Several clinical studies of cancer vaccines for colon cancer are in ongoing clinical trials.

a. Non FDA approved vaccines (Table 4):

Table 4.Non-FDA approved vaccines [42-46]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

FANG Vaccine

NCT01505166

Phase II

Randomized, efficacy study, single blind

Tumor cells

Ad5-hGCC-PADRE vaccine

NCT01972737

Phase I

Safety study, open label

Tumor cells

DEC-205-NY-ESO-1 fusion protein vaccine

NCT01522820

Phase I

Non-Randomized, safety study, open label

NY-ESO-1

EP2101

NCT00054912

Phase I

Non-Randomized, safety study, open label

CAP1-6D, PADRE

AVX701

NCT01890213

Phase I

Safety study, open label

CTL

1. FANG vaccine: Autologous tumor cells transfected with a plasmid expressing recombinant human granulocyte macrophage-colony stimulating factor (rhGM-CSF) and bifunctional short hairpin RNA (bi-shRNA) against furin, with potential immunostimulatory and antineoplastic activities. 

2. Ad5-hGCC-PADRE vaccine: A replication-defective, recombinant adenoviral serotype 5 (Ad5) encoding human guanylyl cyclase C (hGCC) and the synthetic Pan DR epitope (PADRE), with potential antineoplastic and immunomodulating activities. 

3. DEC-205-NY-ESO-1 fusion protein vaccine: A fusion protein, consisting of a fully human monoclonal antibody directed against the endocytic dendritic cell (DC) receptor, DEC-205 linked to the tumor-associated antigen (TAA) NY-ESO-1 with potential immunostimulating and antineoplastic activities.

4. EP2101: A proprietary cancer DNA vaccine that contains multiple natural and modified epitopes derived from the four tumor associated antigens, CEA, HER2/neu, p53, and MAGE 2/3. 

5. AVX701: A cancer vaccine, consisting of alphavirus vector-derived virus-like replicon particles, expressing the 9-amino-acid carcinoembryonic antigen peptide (CAP) 1-6D, with potential antineoplastic activity. Vaccination with this agent may elicit a cytotoxic T lymphocyte (CTL) immune response against CEA-expressing tumor cells.

E. Adoptive cell therapy

In adoptive cell therapy, immune cells are removed from a patient, genetically modified or treated with chemicals to enhance their activity, and then re-introduced into the patient with the goal of improving the immune system’s anti-cancer response.

a. Non FDA approved drugs:

1. Anti-VEGFR2 CAR CD8 plus PBL: A phase I/II trial of anti-VEGFR2 gene engineered CD8+ lymphocytes for colon cancer is ongoing (Table 5).

Table 5.Non-FDA approved adoptive Tcelltherapy [47]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Anti-VEGFR2 CAR CD8 plus PBL

NCT01218867

Phase I, Phase II

Non-Randomized, Safety/Efficacy study, open label

VEGFR2

F. VEGF inhibitor:

1. Aflibercept: Ziv-aflibercept (previously known as Aflibercept) is a recombinant fusion protein, consisting of vascular endothelial growth factor (VEGF)-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin. Ziv-aflibercept injection has been approved by FDA in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC), that is resistant to or has progressed following an oxaliplatin-containing regimen [48].  

Following 4 mg/kg every two weeks i.v. administration, the elimination half-life was approximately 6 days (range 4-7 days). Steady state concentrations were reached by the second dose. An increased risk of hemorrhage, including severe and sometimes fatal hemorrhagic events has been reported in patients treated with Aflibercept. Patients should be monitored for signs and symptoms of gastrointestinal bleeding and other severe bleeding. Not to be administered to patients with severe hemorrhage. Most common adverse events associated with Aflibercept were leukopenia, diarrhea, neutropenia, proteinuria, AST increased, stomatitis, fatigue, thrombocytopenia, ALT increased, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, and headache.

 G. Cancer stemness inhibitor

BBI608: An orally available cancer cell stemness inhibitor with potential antineoplastic activity. Even though the exact target has yet to be fully elucidated, BBI608 appears to target and inhibit multiple pathways involved in cancer cell stemness. This may ultimately inhibit cancer stems cell (CSC) growth, as well as heterogeneous cancer cell growth. CSCs, self-replicating cells that are able to differentiate into heterogeneous cancer cells, appear to be responsible for the malignant growth, recurrence and resistance to conventional chemotherapies (Table 6). 

Table 6.Non-FDA approved cancer stemnessinhibitor [49]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

BBI608

NCT01776307

Phase II

Non Randomized, Safety/Efficacy study, open label

Cancer cell stemness

H. mTOR inhibitor

1. PF-05212384: An agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, PI3K/mTOR kinase inhibitor PKI-587 inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K (Table 7).

Table 7.Non-FDA approved PI3 kinase/mTORinhibitor [50]

2021 Copyright OAT. All rights reserv

Drug

Clinical trial identifier no.

Phase

Study Design

Target

PF-05212384

NCT01937715

Phase II

Randomized, Safety/Efficacy study, open label

PI3K/mTOR

I. Cytokine induced killer cell immunotherapy

Cytokine induced killer cells: A preparation of autologous lymphocytes with potential immunopotentiating and antineoplastic activities. Cytokine-induced killer (CIK) cells are CD3-and CD56-positive, non-major histocompatibility complex (MHC)-restricted, natural killer (NK)-like T lymphocytes, generated ex-vivo by incubation of peripheral blood lymphocytes (PBLs) with anti-CD3 monoclonal antibody, interleukin (IL)-2, IL-1, and interferon gamma (IFN-gamma) and then expanded. When reintroduced back to patients after autologous stem cell transplantation, CIK cells may recognize and kill tumor cells associated with minimal residual disease (MRD). CIK cells may have enhanced cytotoxic activity compared to lymphokine-activated killer (LAK) cells (Table 8).

Table 8.Non-FDA approved cytokine induced killer cells [51,52]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Cytokine induced killer cells

NCT02280278

Phase III

Randomized, Safety/Efficacy study, open label

Cancer cells

Cytokine induced killer cells

NCT01929499

Phase II

Randomized, Safety/Efficacy study, open label

Cancer cells

Conclusion

Our success in treating colon cancer is increasing and advancing with the knowledge of the function of the immune system. Immunotherapy has been a promising development in the past few years. The recent activities have increased our understanding of the tumor microenvironment, various immunotherapeutic modalities or combination therapy (like chemotherapy with immunotherapy). However, the effects of such treatment in cancer patients are still in exploratory phase.  The complete perspective of immunotherapy treatment has not been realized and/or utilized. Proper preclinical and clinical designs are the important pillars in understanding the future of immunotherapy in treating cancer patients.

References

  1. Yeatman TJ (2001) Colon Cancer. Encyclopedia of life sciences. Macmillan Publishers Ltd, Nature Publishing Group.[www.els.net].
  2. Colon cancer. Key statistics about colon cancer. Available at: [http://www.cancer.org/cancer/colonandrectumcancer/detailedguide/colorectal-cancer-key-statistics]. Accessed on 24 Dec 2014
  3. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics. CA Cancer J Clin64: 9-29.[Crossref]
  4. Colon cancer risk factors. Colon cancer alliance. Available at: [http://www.ccalliance.org/colorectal_cancer/riskfactors.html]. Accessed at: 24 Dec 2014.
  5. Markowitz SD, Bertagnolli MM (2009) Molecular origins of cancer: Molecular basis of colorectal cancer. N Engl J Med361: 2449-2460.[Crossref]
  6. Pritchard CC, Grady WM (2011) Colorectal cancer molecular biology moves into clinical practice. Gut60: 116-129.[Crossref]
  7. Caldwell CM, Kaplan KB (2009) The role of APC in mitosis and in chromosome instability. AdvExpMed Biol656: 51-64.[Crossref]
  8. Kastrinos F, Syngal S (2011) Inherited colorectal cancer syndromes. Cancer J17: 405-415.[Crossref]
  9. Woods MO, Younghusband HB, Parfrey PS, Gallinger S, McLaughlin J, et al. (2010) The genetic basis of colorectal cancer in a population-based incident cohort with a high rate of familial disease. Gut59: 1369-1377.[Crossref]
  10. Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, et al. (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat Genet41: 112-117.[Crossref]
  11. Casey G, Conti D, Haile R, Duggan D (2013) Next generation sequencing and a new era of medicine. Gut62: 920-932.[Crossref]
  12. Issa JP (2004) CpG island methylator phenotype in cancer. Nat Rev Cancer4: 988-993.[Crossref]
  13. Donehower LA, Creighton CJ, Schultz N, Shinbrot E, Chang K, et al. (2013) MLH1-silenced and non-silenced subgroups of hypermutated colorectal carcinomas have distinct mutational landscapes. JPathol229: 99-110.[Crossref]
  14. Nieuwenhuis MH, Vogt S, Jones N, Nielsen M, Hes FJ, et al. (2012) Evidence for accelerated colorectal adenoma--carcinoma progression in MUTYH-associated polyposis? Gut61: 734-738.[Crossref]
  15. Colebatch A, Hitchins M, Williams R, Meagher A, Hawkins NJ, et al. (2006) The role of MYH and microsatellite instability in the development of sporadic colorectal cancer. Br J Cancer95: 1239-1243.[Crossref]
  16. Ogino S, Chan AT, Fuchs CS, Giovannucci E (2011) Molecular pathological epidemiology of colorectal neoplasia: an emerging transdisciplinary and interdisciplinary field. Gut60: 397-411.[Crossref]
  17. Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, et al. (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med360: 1408-1417.[Crossref]
  18. Liao X, Lochhead P, Nishihara R, Morikawa T, Kuchiba A, et al. (2012) Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med367: 1596-1606.[Crossref]
  19. FDA approved label Erbitux (Cetuximab). Manufactured by Eli Lilly Company. Last updated on 2013, Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125084s242lbl.pdf. [Crossref]
  20. FDA approved label Avastin (Bevacizumab). Manufactured by Genentech, Inc. Last updated on 2014, Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125085s305lbl.pdf
  21. FDA approved label Vectibix® (Panitumumab). Manufactured by Amgen Inc. Last updated on 2014, Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125147s194lbl.pdf.
  22. http://www.medicines.org.uk/emc/medicine/29765
  23. National Cancer Institute (NCI); National Cancer Institute (NCI). Edrecolomab in Treating Patients With Stage II Colon Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015FEB27.
  24. Peking University; Peking University. Study of Nimotuzumab to Treat Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  25. EMD Serono; EMD Serono. Sym004 vs Standard of Care in Subjects With Metastatic Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  26. Celldex Therapeutics; Celldex Therapeutics. A Dose Escalation and Cohort Expansion Study of Anti-CD27 (Varlilumab) and Anti-PD-1 (Nivolumab) in Advanced Refractory Solid Tumors. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  27. University of Pittsburgh; Dr. James Lee, University of Pittsburgh. A Phase 2 Study of Pembrolizumab (MK-3475) in Combination WithAzacitidine in Subjects With Chemo-refractory Metastatic Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  28. Bristol-Myers Squibb; Bristol-Myers Squibb. A Study of Nivolumab and NivolumabPlusIpilimumab in Recurrent and Metastatic Colon Cancer (CheckMate 142). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  29. Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center. Evaluate the Efficacy of MEDI4736 in Immunological Subsets of Advanced Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  30. FDA approved label Stivarga (Regorafenib). Manufactured by Bayer Health Care Pharmaceuticals Inc. Last updated on 2013, Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203085s001lbl.pdf.
  31. Southwest Oncology Group; Southwest Oncology Group. S1406 Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015FEB27.
  32. National Cancer Institute (NCI); National Cancer Institute (NCI). ImatinibMesylate in Treating Patients With Stage IV Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015FEB27.
  33. National Cancer Institute (NCI); National Cancer Institute (NCI). Erlotinib in Treating Patients With Recurrent or Metastatic Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015FEB27.
  34. Hutchison Medipharma Limited; Hutchison Medipharma Limited. A Phase III Trial Evaluating Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients (FRESCO). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  35. Jiangsu HengRui Medicine Co., Ltd.; Jiangsu HengRui Medicine Co., Ltd. A Study of Famitinib in Patients With Advanced Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  36. BoehringerIngelheim; BoehringerIngelheim. Nintedanib (BIBF 1120) vs Placebo in Refractory Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  37. Washington University School of Medicine;;; Washington University School of Medicine. Pacritinib to Inhibit JAK/STAT Signaling in Refractory Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  38. Jiangsu Chia-tai Tianqing Pharmaceutical Co.,Ltd; Jiangsu Chia-tai Tianqing Pharmaceutical Co.,Ltd. Study of Anlotinib in Patients With Metastatic Colorectal Cancer(mCRC)(ALTER0703). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  39. Incyte Corporation; Incyte Corporation. Study of Ruxolitinib in Colorectal Cancer Patients. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  40. National Cancer Institute (NCI); National Cancer Institute (NCI). Akt Inhibitor MK2206 in Treating Patients With Previously Treated Colon or Rectal Cancer That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  41. Oncoceutics, Inc.; Oncoceutics, Inc. A First-in-man Phase I/II Study of Oral ONC201 in Patients With Advanced Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  42. Gradalis, Inc.; Gradalis, Inc. Randomized Phase II Adjuvant Chemotherapy ± FANG™ in Colorectal Carcinoma with Liver Metastases. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2014DEC29.
  43. Thomas Jefferson University; Thomas Jefferson University. Phase I Study of Ad5-hGCC-PADRE) in Stage I and II Colon Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2014DEC29.
  44. Roswell Park Cancer Institute; Roswell Park Cancer Institute. Vaccine therapy with or without Sirolimus in treating patients with NY-ESO-1 expressing solid tumors. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2014DEC29.
  45. Epimmune; Epimmune. An Open Label Study of a Peptide Vaccine in Patients With Stage III Colon Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015FEB27.
  46. Duke University; Michael Morse, MD, Duke University. Immunotherapy With CEA(6D) VRP Vaccine (AVX701) in Patients With Stage III Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  47. National Cancer Institute (NCI); National Institutes of Health Clinical Center. CAR T cell receptor Immunotherapy targeting VEGFR2 for patients with metastatic cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2014DEC29.
  48. FDA approved label Zaltrap® (Aflibercept). Manufactured by sanofi-aventis U.S. LLC Bridgewater. Last updated on 2013, Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125418s020lbl.pdf
  49. Boston Biomedical, Inc; Boston Biomedical, Inc. A Study of BBI608 in Adult Patients With Advanced Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  50. Pfizer; Pfizer. A Study Of PF-05212384 Plus FOLFIRI Versus Bevacizumab Plus FOLFIRI In Metastatic Colorectal Cancer. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  51. Sun Yat-sen University; Xiao-Jun Wu, Sun Yat-sen University. Cytokine-induced Killer Cell Immunotherapy for Surgical Resected Stage III Colorectal Cancer Patients After Chemotherapy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.
  52. Yanjuan Zhu; Yanjuan Zhu, Guangdong Provincial Hospital of Traditional Chinese Medicine. Efficacy of Adjuvant Cytokine-induced Killer Cells in Colon Cancer (CIKCC). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2015APRIL22.

Editorial Information

Editor-in-Chief

Masayoshi Yamaguchi
Emory University School of Medicine

Article Type

Review Article

Publication history

Received: March 01, 2016
Accepted: March 30, 2016
Published: April04, 2016

Copyright

©2016Allen T.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Allen T, Al-Hadeethi A (2016)Immunotherapy and colon cancer. Integr Cancer Sci Therap. 3: DOI: 10.15761/ICST.1000180.

Corresponding author

Abdullateef Al-Hadeethi

Global Allied Pharmaceuticals, Gardens St., Amman, 11195 , Jordan, Tel: 00962 797945820.

E-mail : dr.abdulateef@gmail.com

Table 1.Non-FDA approved monoclonal antibodies [23-25]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Edrecolomab

NCT00002968

Phase III

Randomized, Safety/Efficacy study, open label

EpCAM

Nimotuzumab

NCT00972465

Phase II

Non Randomized, Safety study, open label

EGFR

Sym004

NCT02083653

Phase II

Randomized, Safety/Efficacy study, open label

EGFR

Table 2.Non-FDA approved checkpoint inhibitors [26-29]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Varlilumab

NCT02335918

Phase I, Phase II

Safety/Efficacy study, open label

CD27

 Pembrolizumab

NCT02260440

Phase II

Safety/Efficacy study, open label

PD-1

Nivolumab

NCT02060188

Phase I, Phase II

Non Randomized, Efficacy study, open label

PD-1

MEDI4736

NCT02227667

Phase II

Safety/Efficacy study, open label

B7H1

Table 3.Non-FDA approved kinase inhibitors [31-41]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Vemurafenib

NCT02164916

Phase II

Randomized, efficacy study, open label

BRAF (V600E) kinase

Imatinib

NCT00041340

Phase II

Safety/Efficacy study, open label

TK

Erlotinib  hydrochloride

NCT00032110

Phase II

Safety/Efficacy study, open label

EGFR

Fruquintinib

NCT02314819

Phase III

Randomized, Efficacy study, Double blind

VEGFRs 1, 2, and 3

Famitinib

NCT01762293

Phase II

Randomized, Safety/Efficacy study, double blind

RTK

BIBF 1120

NCT02149108

Phase III

Randomized, Safety/Efficacy study, double blind

VEGFR, FGFR, PDGFR

 Pacritinib

NCT02277093

Phase II

Safety/Efficacy study, open label

JAK2, JAK2V617F

Anlotinib

NCT02332499

Phase II, Phase III

Randomized, Safety/Efficacy study, double blind

RTK

Ruxolitinib

NCT02119676

Phase II

Randomized, double blind

JAK 1 and 2

MK2206

NCT01802320

Phase II

Efficacy study, open label

Proteinkinase B

ONC201

NCT02038699

Phase I, Phase II

Safety/Efficacy study, open label

Akt/ERK

Table 4.Non-FDA approved vaccines [42-46]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

FANG Vaccine

NCT01505166

Phase II

Randomized, efficacy study, single blind

Tumor cells

Ad5-hGCC-PADRE vaccine

NCT01972737

Phase I

Safety study, open label

Tumor cells

DEC-205-NY-ESO-1 fusion protein vaccine

NCT01522820

Phase I

Non-Randomized, safety study, open label

NY-ESO-1

EP2101

NCT00054912

Phase I

Non-Randomized, safety study, open label

CAP1-6D, PADRE

AVX701

NCT01890213

Phase I

Safety study, open label

CTL

Table 5.Non-FDA approved adoptive Tcelltherapy [47]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Anti-VEGFR2 CAR CD8 plus PBL

NCT01218867

Phase I, Phase II

Non-Randomized, Safety/Efficacy study, open label

VEGFR2

Table 6.Non-FDA approved cancer stemnessinhibitor [49]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

BBI608

NCT01776307

Phase II

Non Randomized, Safety/Efficacy study, open label

Cancer cell stemness

Table 7.Non-FDA approved PI3 kinase/mTORinhibitor [50]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

PF-05212384

NCT01937715

Phase II

Randomized, Safety/Efficacy study, open label

PI3K/mTOR

Table 8.Non-FDA approved cytokine induced killer cells [51,52]

Drug

Clinical trial identifier no.

Phase

Study Design

Target

Cytokine induced killer cells

NCT02280278

Phase III

Randomized, Safety/Efficacy study, open label

Cancer cells

Cytokine induced killer cells

NCT01929499

Phase II

Randomized, Safety/Efficacy study, open label

Cancer cells