Although colorectal cancer (CRC) incidence and mortality continue to decline in the United States, the disease continues to be both a national and worldwide concern based on it being the fourth most common cause of cancer and second leading cause of cancer-related mortality worldwide. 1,2

At the time of diagnosis, close to two-thirds of patients undergo surgical resection, however, up to 50% of patients can develop recurrence leading to increased risk of mortality.3 In addition, adjuvant chemotherapy has limited benefit in patients with early-stage disease (stages 1 and 2, node negative), therefore, there is an overwhelming need for further treatment options. 

Immunotherapies are being evaluated across multiple cancer subtypes. Unfortunately, there has been limited success in using immunotherapies such as pembrolizumab and nivolumab in patients with CRC, as the most consistent data have been limited to patients with microsatellite instability (MSI).4 These checkpoint inhibitors have not shown efficacy in patients with CRC whom have microsatellite stable (MSS) disease, which represents the overwhelming majority of patients (85%).3 

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Although the immunotherapy agents to date have not provided significant results in patients with CRC, there are other options within the immune system that are being thoroughly researched in CRC. One such development includes targeting certain antigens found within CRC cells to promote an immune reaction directed against the cancer. 

Guanylyl cyclase C (GUCY2C) is one such antigen that is a membrane receptor found predominantly in intestinal cells and is significantly overexpressed in CRC.3 Only until recently, most of the research involving GUCY2C in CRC has been performed in animal models such as mice, which have included using adenovirus (Ad5) to deliver GUCY2C-based vaccines. These preclinical studies have shown a strong CD8-positive T-cell response that has prevented metastases and promoted a “split tolerance,” in which only CD8-positive T cells are induced (and not CD4-positive cells), thereby limiting many autoimmunity concerns.

Recently, a group of researchers published the first-in-man study evaluating the Ad5-GUCY2C vaccine in patients with CRC.3 The authors recruited 10 patients for this phase 1 study with early-stage CRC (stages 1 or 2; node negative) that had undergone surgical resection but had not received chemotherapy or radiation therapy.  These patients received a single intramuscular injection of 1011 viral particles followed by extensive safety follow-up including clinic visits, phone calls, and bloodwork.

Forty percent of patients demonstrated GUCY2C-specific T-cell responses, all of which were CD8-positive T cells. Ten percent of patients developed antibodies after vaccination. Patients with preexisting neutralizing antibodies to the Ad5 vector had worse vaccine-induced immune responses. With respect to safety, all 10 patients completed the study and there were no adverse events classified as greater than grade 1. The most commonly reported adverse events included chills/rigor (20%) and injection site reaction/arm swelling (20%). All other adverse events were reported at 10% (dizziness, diaphoresis, aches, and fever). 

This study raised several interesting points. The authors were able to show a CD8-positive–specific T-cell response in 40% of patients along with limited autoimmunity and minimal adverse events. The presence of preexisting neutralizing antibodies to the Ad5 limited immune response, therefore, future studies could potentially consider the evaluation of different vectors or the screening of patients for these antibodies to help identify the patients most likely to respond. The patients received only 1 injection, therefore, it would be interesting to evaluate the potential role of multiple injections in the setting of a dose-response study. Although these results are relatively promising, it is important to note that this study included a limited number of patients, was a phase 1 study, and had limited clinical end points, all of which can be further examined in future studies.

In the future, additional vaccine-based CRC studies will aim to increase the number of patients and long-term follow-up to further evaluate both safety and efficacy end points.  Depending on these results, it is possible that additional gastrointestinal malignancies could be targeted with vaccine-based treatments as well.

References

  1. Cronin KA, Lake AJ, Scott S, et al. Annual report to the nation of the status of cancer, part I: national cancer statistics. Cancer. 2018;124(13):2785-2800.
  2. Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177-193.
  3. Snook AE, Baybutt TR, Xiang B, et al. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. J Immunother Cancer.  2019;7(1):104.
  4. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response to solid tumors to PD-1 blockade. Science. 2017;357(6349):409-413.