View source for Section 4.1: Agents targeting CSC-associated surface biomarkers in clinical trials (from DOI: 10.1038/s41392-020-0110-5)

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<b>From publication:</b> "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8<br> https://doi.org/10.1038/s41392-020-0110-5 <br><h3><u>Section 4.1: Agents targeting CSC-associated surface biomarkers in clinical trials</u></h3><p>Monoclonal antibodies (mAbs) that target CSC-specific surface biomarkers have become an emerging technology for cancer therapy. Rituximab, a CD20 mAb, is an active agent for the treatment of follicular lymphoma and mantle-cell lymphoma, but some serious adverse reactions still occur. Subsequently, to improve the availability and affordability of radioimmunotherapy for refractory or recurrent non-Hodgkin's lymphoma (NHL), a phase II clinical trial for a radioiodine replacement of rituximab was carried out, which showed a response rate of 71% and a complete remission rate of 54% in 35 patients, with only two cases of grade IV hematologic toxicity observed. Encouragingly, alemtuzumab, a humanized CD52 antibody, has been approved for the treatment of chronic lymphocytic leukemia (CLL) in patients who failed to respond to alkylating agents and purine. Furthermore, the combination of the CD20 and CD52 antibodies in the treatment of refractory CLL was safe, nontoxic, feasible, and positive. Another antibody drug, relabeled bivatuzumab, is an anti-CD44v6 mAb, which was found to be safe when it was used for the treatment of head and neck SCC. These results have been obtained in subsequent clinical research and safety/efficacy studies. Unfortunately, in a stage I dose escalation study with the CD44v6 antibody, one patient with head and neck SCC of the esophagus suffered deadly skin toxicity.</p><p>Several CD123 antibodies have been developed, XmAb14045 and MGD006, and were designed with biospecific effects against CD3 and CD123. Talacotuzumab is also effective against CD16 and CD123. CSL360, another CD123 antibody, was used to treat relapsed, refractory, or high-risk acute myeloid leukemia (AML) and displayed no anti-leukemic activity in most cases. SL-401, another CD123 antibody, was used to treat blastic plasmacytoid dendritic cell neoplasm patients. The results showed major positive responses in seven out of nine patients, including five complete responses and two partial responses. An ongoing phase II study of SL-401 in 29 patients with blastic plasmacytoid dendritic cell neoplasms demonstrated robust single-agent activity with an 86% overall response rate. The latest antibodies against CSC surface markers, such as XmAb14045 (NCT02730312), flotetuzumab (NCT02152956), and talacotuzumab (NCT02472145), are also in clinical study. Furthermore, several other markers that can distinguish LSCs from other cells are under clinical development, such as IL-1 receptor accessory protein, CD27/70, CD33, CD38, CD138, CD93, CD99, C-type lectin-like molecule-1, and T cell immunoglobulin mucin-3.</p><p><i><b>Table data 3: </b>Drug name Antibody target Condition Sample size Highest status NCT number Current status Surface antigens Catumaxomabr (emovab) EpCAM/CD3 Ovarian cancer II 44 NCT00189345 Completed Tagraxofusp SL-401 CD123 Acute myeloid leukemia I 36 NCT03113643 Recruiting KHK2823 I 39 NCT02181699 Terminated Talacotuzumab III 326 NCT02472145 Completed, has results SGN-CD123A I 17 NCT02848248 Terminated IMGN632 II 155 NCT03386513 Recruiting XmAb14045 CD123/CD4 II 105 NCT02730312 Recruiting MGD006 CD123/CD3 II 179 NCT02152956 Recruiting JNJ-63709178 III 326 NCT02472145 Completed, has results CSL362 CD124 I 30 NCT01632852 Completed TTI-621 CD47 Solid tumor I 260 NCT02663518 Recruiting Hu5F9-G4 Solid tumor I 88 NCT02216409 Completed IBI188 Advanced malignancies I 42 NCT03763149 Recruiting CC-90002 Hematologic neoplasms I 28 NCT02641002 Terminated AO-176 Solid tumor I 90 NCT03834948 Recruiting SRF231 Solid tumor I 148 NCT03512340 Recruiting Bivatuzumab mertansine Metastatic breast cancer I 24 NCT02254005 Completed Vadastuximab talirine (SGN-CD33A) CD33 Acute myelogenous leukemia I 195 NCT01902329 Completed IMGN779 I 62 NCT02674763 Completed Mylotarg (gemtuzumab ozogamicin) ECG IV 56 NCT03727750 Recruiting RO5429083 CD44 Malignant solid tumors I 65 NCT01358903 Completed SPL-108 Ovarian cancer I 18 NCT03078400 Recruiting Salazosulfapyridine CD44V4 Non-small-cell lung cancer I UMIN000017854 AMC303 CD44V6 Solid tumor I 55 NCT03009214 Recruiting Immune checkpoints Ipilimumab CTLA-4 Non-small-cell lung cancer II 24 NCT01820754 Completed, has results Nivolumab PD-1 Glioblastoma multiforme II 29 NCT02550249 Completed Pembrolizumab II 80 NCT02337491 Completed, has results Cemiplimab II 30 NCT04006119 Recruiting Idarubicin Acute myeloid leukemia II 51 NCT01035502 Completed Sym021 Solid tumor lymphomas I 102 NCT03311412 Recruiting Durvalumab Solid tumors II 124 NCT02403271 Completed, has results Atezolizumab PD-L1 Non-small-cell lung cancer III 1225 NCT02008227 Completed, has results Avelumab Recurrent glioblastoma II 52 NCT03291314 Completed Sym023 Tim3 Solid tumor I 48 NCT03489343 Recruiting ARGX-110 CD70 Acute myeloid leukemia II 36 NCT03030612 Active, not recruiting Varlilumab (CDX-1127) Solid tumors II 175 NCT02335918 Completed Sym022 LAG3 Solid tumor I 30 NCT03489369 Recruiting MGD013 CD70/LAG3 Solid tumors I 255 NCT03219268 Recruiting </i></p><p><i><b>Table 3 caption: </b>Agents targeting CSC-associated surface markers in ongoing clinical trials</i></p><p>EpCAM, a common CSC biomarker, has also received attention in clinical trials. Adecatumumab, an EpCAM antibody, was used in patients with hormone-resistant prostate cancer, and the results showed that the EpCAM-specific antibody has great clinical potential. Catumaxomab, a multifunctional mAb against EpCAM, binds and recognizes EpCAM and the T cell antigen CD3 (anti-EpCAM x anti-CD3). Intraperitoneal injection of catumaxomab to treat EpCAM-positive ovarian cancer and malignant ascites has shown high efficacy in killing cancer cells and reducing the formation of ascites. Catumaxomab has been used in non-small-cell lung cancer and also had a good survival rate. However, other types of EpCAM antibodies, such as edrecolomab and adecatumumab, have minimal efficacy in colorectal and breast cancers. Combining EpCAM antibodies with chimeric antigen receptor T cell (CAR-T) technology has also been used in various types of cancers in phase I trials, such as NCT02915445, NCT03563326, NCT02729493, and NCT02725125. With a deeper understanding of CSC surface biomarkers, there has been significant progress in developing antibodies targeting CSCs (Table 2). However, CSC surface phenotypes can vary in different patients or different cancers, and different CSC populations with different phenotypes might coexist. CSCs also diverge or evolve into different cancer cells, acquiring distinct phenotypes upon relapse. Therefore, the strategies used in clinical trials should be determined according to the phenotypes of the different cancers. At the same time, combining different surface antibodies with relevant chemotherapy drugs can achieve an ideal therapeutic effect.</p>