Table 3.
Summary of important studies that targeted immune cells for treating metastatic CRC
| Immunotherapy | Targeted Antigen |
Adjuvants/immune modulator |
Study population and size |
Remarks | Reference |
|---|---|---|---|---|---|
| Ipilimumab | CTLA-4 | None | 3 colon cancer | Tregs were depressed early in treatment, but no increase in CD8+ T-cell responses. |
[79] |
| Tremelimumab | CTLA-4 | None | 45 treatment-refractory CRC |
One patient demonstrate partial response, while others experienced enterocolitis. |
[80] |
| MDX-1106 | PD-1 | None | 14 advanced CRC and 25 other cancers |
One patient demonstrated durable complete response. Inflammatory colitis or adverse events occurred in 3 patients. |
[82] |
| BMS-936558 | PD-1 | None | 19 advanced CRC | No objective responses in CRC patients. One CRC patient died from treatment. |
[83] |
| BMS-936559 | PD-L1 | None | 18 advanced CRC | No objective responses in CRC patients. | [84] |
| AIT (Lymph node and peripheral lymphocytes) |
Sonicated tumor extract |
T-cell growth factors and OK-432 (Streptococcal preparation) |
19 gastric or colorectal cancers with metastasis to the liver |
2 patients demonstrated complete response, 4 with partial. |
[91] |
| AIT (Tumor- associated lymphocytes) |
Autologous tumor |
IL-2 | 14 stage IV gastric and colorectal cancer |
3 patients were protected from TCR-ζ down- regulation and experienced clinical response. |
[93] |
| AIT (TILs) | Untargeted | IL-2 | 14 metastatic CRC | No difference was observed from control group. |
[92] |
| AIT (CD4+ T-cells) | Autologous tumor |
IL-2 | 16 CRC | 4 of 9 stage IV patients experienced complete remission. |
[94] |
| CAR (PBLs) | ERBB2 | Anti-CD3 and IL-2 | 1 colon cancer | Patient died from respiratory distress. | [98] |
| CAR (PBLs) | CEA | Anti-CD3 and IL-2 | 3 metastatic CRC | 1 patient demonstrated regression of lung and liver metastasis. All patients experienced severe inflammatory colitis. |
[99] |
| Lymphodepletion | Untargeted | Cyclophosphamide | 27 CRC | Increased IFN-γ-producing T-cells. | [102] |
| Allo-SCT | Untargeted | Busulfan and fludarabine | 4 metastatic CRC | No significant toxicities were detected. | [103] |
| Allo-SCT | Untargeted | Busulfan and fludarabine | 1 chemoradiotherapy resistant CRC |
Severe inflammatory cell infiltration into mucosa. Patient did not achieve remission. |
[104] |
| Allo-SCT | Untargeted | Fludarabine and total body irradiation |
3 CRC and 4 other cancers |
3 patients demonstrated stable disease for at least 18 months. |
[106] |
| Allo-SCT | Untargeted | Fludarabine and total body irradiation |
1 CRC | Patient died of pneumonia 4 months after transplant. Most metastases were necrotic with few remaining tumor cells. |
[108] |
| Allo-SCT | Untargeted | Fludarabine and total body irradiation |
15 metastatic CRC | 3 patients demonstrated stable disease and 1 with partial response. |
[109] |
| Allo-SCT | Untargeted | Fludarabine and total body irradiation |
6 colon cancer and 12 other cancers |
2 colon cancer patients demonstrated repression. 4 patients died from transplant. |
[110] |
| Allo-SCT | Untargeted | Combinations of cyclophosphamide, busulfan, fludarabine, and total body irradiation |
39 refractory metastatic CRC |
6 stable disease and 2 partial response. | [111] |
| DNA vaccine | CEA | None | 17 metastatic CRC | No clinical response. 4 patients demonstrated increased numbers of circulating CEA-specific lymphocytes. |
[114] |
| Peptide vaccine | β-hCG | Diphtheria toxoid | 77 metastatic CRC | The 56 patients who generated antibodies generally lived longer. |
[115] |
| Peptide vaccine | G-17 | Diphtheria toxoid | 161 CRC | 3 partial responses and 32 stable disease. Patients who generated antibodies generally lived longer. |
[116] |
| Peptide vaccine | CEA | Ad5 | 25 advanced CRC | 12 patients lived past 12 months. Did not report impact on survival. |
[117] |
| Autologous tumor cell vaccine |
Autologous tumor cells |
BCG | 80 CRC | Colon cancer patients demonstrated improved survival. Rectal cancer patients did not improve. |
[118] |
| Autologous tumor cell vaccine |
Autologous tumor cells |
BCG | 128 colon cancer | Vaccinated patients demonstrated fewer reoccurrences. |
[119] |
| Autologous tumor cell vaccine |
Autologous tumor cells |
NDV | 23 metastatic CRC | Vaccinated patients demonstrated fewer reoccurrences. |
[120] |
| Autologous tumor cell vaccine |
Autologous tumor cells |
NDV | 25 metastatic CRC | Vaccinated patients demonstrated improved metastasis-free and overall survival. |
[121] |
| Peptide vaccine | CEA | GM-CSF | 9 CRC | All patients receiving GM-CSF generated IFN- γ secreting T-cells. No autoimmunity was reported. |
[123] |
| Peptide vaccine | Ep-CAM | GM-CSF and ALVAC | 12 CRC | The GM-CSF patients strongly generated anti- Ep-CAM-specific Type-1 responses. |
[124] |
| DC vaccine | CAP-1 | GM-CSF and IL-4 | 21 CRC | 1 patient demonstrated minor response and 1 demonstrated stable disease. No observable autoimmunity. |
[126] |
| DC vaccine | CAP-1 | GM-CSF and IL-4 | 17 metastatic CEA- expressing cancer |
No difference between peptide and mRNA loading. |
[134] |
| DC vaccine | CAP-1 | GM-CSF, IL-4,PGE2, TNF- α, IL-1β, and IL-6 |
16 metastatic CEA- expressing cancer |
8 of 11 receiving peptide demonstrated T-cell responses. None of the mRNA group responded. |
[133] |
| DC vaccine | CEA | GM-CSF, IL-4,PGE2, TNF- α, IL-1β, and IL-6 |
7 CRC and 2 lung cancer |
CEA-reactive CD8+ T-cells were expanded. No tumor repression was observed. |
[129] |
| DC vaccine | CEA | GM-CSF, IL-4,PGE2, and TNF-α |
10 metastatic CRC | CEA-reactive CD8+ T-cells were expanded in 7 patients. 2 patients demonstrated stable disease for at least 12 months. |
[130] |
| DC vaccine | CEA | GM-CSF, IL-4, TNF-α, and IFN-α |
10 metastatic CEA- expressing cancer |
2 patients responded with positive delayed-type hypersensitivity test. |
[131] |
| DC vaccine | CAP-1 | GM-CSF, IL-4, TNF-α, and IFN-α |
7 stage III CRC | 4 of 7 patients generated CEA-specific T-cell responses. |
[132] |
| DC vaccine | CEA | Flt3L | 9 colon, 1 rectum, and 2 lung |
2 patients demonstrated complete response, and 2 with stable disease. |
[127] |
| DC vaccine | CEA and other peptides |
GM-CSF, IL-13, Klebsiella- derived cell wall fraction, and IFN-γ |
11 advanced CRC | 3 patients generated CEA-specific T-cells. | [128] |
| DC vaccine | CAP-1 | GM-CSF, IL-4, and poxvector containing B7.1 (CD80), ICAM-1 (CD54), and LFA-3 (CD58) |
11 CRC and 3 non- small lung cancer |
10 patients generated CEA-specific T-cells. No toxicities were reported. |
[139] |
AIT, Adoptive Immunotherapy; Allo-SCT, allogeneic stem-cell transplantation; ALVAC, replicative-deficient recombinant avipoxvirus; BCG, bacillus Calmette-Guérin; β-hCG, beta-human chorionic gonadotropin CAP-1, carcinoembryonic antigen peptide-1; CAR, chimeric antigen receptor; CEA, carcinoembryonic antigen; CRC, colorectal cancer; CTLA-4, cytotoxic T-lymphocyte antigen 4; DC, dendritic cells; ERBB2; Ep-CAM, epithelial cellular adhesion molecule; Flt3L, Flt3-ligand G-17, gastrin-17; GM-CSF, granulocyte macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule-1; IFN, interferon; LFA-3, leukocyte function-associated antigen-3; NDV, Newcastle disease virus; PBLs, peripheral blood lymphocytes; PD-1/PD-1L, programmed death receptor-1/ligand-1; PGE2, prostaglandin E2; TCR, T-cell receptor; TILs, Tumor-infiltrating lymphocytes; TNF, tumor necrosis factor; Tregs, regulatory T-cells