br this combination Furthermore repeat
this combination. Furthermore, repeat studies have shown that a small percentage of these tumors exhibit durable complete regres-sion without the need for further treatment following an initial 2 cycles. This combination also proved safe at target dosing with less than 10% decrease in weight of mice treated during the described experiments.
Although the function of MSLN E64 in malignancy has yet to be fully determined and a large-scale study of the clinical and mutational implications of MSLN expression in CRC still needs to be performed, clinical studies in pancreatic and ovarian cancer have shown that those tumors expressing MSLN tend to metastasize more readily and aggressively than their counterparts.27-30 MSLN has also been implicated in the spread of ovarian cancer to the peritoneum through its interaction with MUC16.31 MSLN expression has also been associated with a higher rate of KRAS mutation in lung cancer.32 RIT therapy targeting MSLN plays a role in treating such malignancies that are not candidates for surgical
Figure 6 Female Nude Mice Were Inoculated Subcutaneously With SW48 Cells in the Right Flank and Underwent Treatment Beginning at 7 Days Post Inoculation (Plotted as Day 0). Each Data Point Represents the Average Tumor Volume for n [ 8 Animals Treated With LMB-100, Oxaliplatin, Combination Oxaliplatin and LMB-100, or Phosphate-buffered Saline Control. There Is a Significant Difference Between Groups Treated With Recombinant Immunotoxin Therapy (RIT) Monotherapy or Combination RIT-Oxaliplatin Therapy (P < .05) Beginning on Day 12 (Indicated by *) and Persisting Throughout the Experiment. There Is No Significant Difference Noted Between Combination Therapy or Combination RIT Therapy
Adam Cerise et al
MSLN is a cell surface glycoprotein expressed at high level on many malignancies including pancreatic adenocarcinoma, stomach cancer, ovarian cancer, and epithelioid mesothelioma. Recent data has shown that MSLN is expressed at clinically relevant levels on the surface of CRC. MSLN-targeted RITs consist of an anti-MSLN Fv fused to the catalytic domain of PE.
In a nude mouse model, MSLN-targeted RIT treatment of SW48 CRC tumors resulted in a significant decrease in tumor volume as a single agent and in combination therapy with acti-nomycin D. MSLN-targeted RIT resulted in > 90% tumor volume reduction with 50% complete regressions.
In conclusion, MSLN-targeted RIT therapy has a role in CRC that has previously been overlooked, and in combination with actinomycin D, can produce significant tumor regression including complete and durable regression.
resection or do not respond to standard of care chemotherapeutics. Furthermore, the combination of RIT therapy and chemothera-peutics with novel mechanisms of action such as actinomycin D are another potential strategy to treat aggressive and refractory malignancies.
In conclusion, MSLN-targeted RIT therapy has a role in CRC that has previously been overlooked; and in combination with actinomycin D, can produce significant tumor regression including complete and durable regression.
Clinical Practice Points
According to recent statistics from the American Cancer Society, CRC is the third most common cancer diagnosed in both men and women in the United States. The current estimates for the number of new CRC cases in the United States for 2019 are 101,420 of colon cancer and 44,180 of rectal cancer. It is also the second most common cause of death owing to cancer in the Western world. It is expected to cause about 51,020 deaths during 2019. Despite recent progress on early detection and therapeutic advances, new treatment options are needed to reduce the mortality rate from Condensation reaction cancer.
The authors would like to acknowledge all those in the Labora-tory of Molecular Biology, Alewine Lab Group, and Pastan Lab Group for their technical and experimental guidance. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.
The authors declare no conflict of interest.
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3. Wayne AS, Shah NN, Bhojwani D, et al. Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leu-kemia. Blood 2017; 130:1620-7.
4. Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci U S A 1996; 93:136-40.