Kaitlin M. Peace

Cancer vaccines in colon and rectal cancer over the last decade: lessons learned and future directions

ABSTRACT Introduction: Great advances have been made in screening for and treatment of colorectal cancer (CRC), but recurrence rates remain high and additional therapies are needed. There is great excitement around the field of immunotherapy and many attempts have been made to bring immunotherapy to CRC through a cancer vaccine. Areas covered: This is a detailed review of the last decade’s significant CRC vaccine trials. Expert commentary: Monotherapy with a CRC vaccine is likely best suited for adjuvant therapy in disease free patients. Vaccine therapy elicits crucial tumor infiltrating lymphocytes, which are lacking in microsatellite-stable tumors, and therefore may be better suited for these patients. The combination of CRC vaccines with checkpoint inhibitors may unlock the potential of immunotherapy for a much broader range of patients. Future studies should focus on vaccine monotherapy in correctly selected patients and combination therapy in more advanced disease.

Therapeutic Cancer Vaccines for Melanoma

Melanoma has long been a prominent focus of investigation for cancer immunotherapy due to its intrinsically immunogenic nature, typically a consequence of a high mutational load. Furthermore, tumor infiltration by lymphocytes provides evidence of endogenous immune activity, as does the spontaneous regression described in some tumors. Conversely, the melanoma microenvironment promotes upregulation of immunosuppressive cells (myeloid-derived suppressor cells and regulatory T cells) and cytokines (such as IL-6, IL-10, TNFα, TGFβ, and VEGF) facilitating evasion of the immune response. The tumor microenvironment contains several targets for immunomodulation that are under active investigation. In this chapter, we will explore the development of immunotherapy for the treatment of melanoma, beginning with early, nonspecific immunomodulation through more recent advances in melanoma vaccines with specific discussion of several phase III clinical trials for peptide, viral, dendritic cell, and whole tumor cell-based vaccines.

Effects of HLA status and HER2 status on outcomes in breast cancer patients at risk for recurrence – Implications for vaccine trial design

Immunotherapy, using peptide-based cancer vaccines is being studied to assess its potential in breast cancer. Trials of HLA-restricted peptide vaccines have been difficult to enroll given HLA subtype restrictions. It is necessary to determine the prognostic significance of HLA-status in breast cancer if patients who are ineligible to receive a vaccine due to their HLA-status are used as controls. The impact of targeted tumor associated antigen expression, when it effects eligibility is also important. We examined control patients from two randomized phase II trials that tested HER2-peptide vaccines to determine the effect of HLA-A2 status and HER2 expression on disease-free survival. The analysis showed that HLA-A2-status does not affect disease-free survival, regardless of HER2 expression suggesting that HLA-A2 negative patients can be used as control patients. Additionally, HER2 over-expression was associated with a better disease-free survival in this population, underscoring the need for additional therapies in HER2 low-expressing breast cancer. ClinicalTrials.gov Identifier: NCT00524277.

Rectal Trauma: Evidence-Based Practices

The management of rectal trauma has often been lumped in with colon trauma when, in fact, it is a unique entity. The anatomic nature of the rectum (with its intra- and extraperitoneal segments) lends itself to unique circumstances when it comes to management and treatment. From the four Ds (debridement, drainage, diversion, and distal irrigation), the management of rectal trauma has made some strides in light of the experiences coming out of the recent conflicts overseas as well as some rethinking of dogma. This article will serve to review the anatomy and types of injuries associated with rectal trauma. A treatment algorithm will also be presented based on our current literature review. We will also address controversial points and attempt to give our opinion in an effort to provide an update on an age-old problem.

Abstract CT162: Pre-specified interim analysis in a prospective, randomized phase II trial of trastuzumab vs trastuzumab + NeuVax to prevent breast cancer recurrence in HER2+ breast cancer patients

Introduction: The HER2-targeted monoclonal antibody, trastuzumab (Tz), is standard of care (SOC) for HER2-positive (HER2+) breast cancer (BCa) and has been shown to reduce recurrence. We have previously shown that NeuVax (E75 peptide + GM-CSF), a HER2-targeted peptide vaccine, is safe, immunogenic, and may have synergistic clinical efficacy when combined with Tz. Given the known cardiac toxicity of Tz, there is concern that adding a HER2-directed vaccine to Tz therapy may exacerbate this effect. We are currently enrolling patients (pts) in a multi-center, prospective, randomized, single-blinded, placebo-controlled phase II trial combining Tz and Neuvax in the adjuvant setting to prevent recurrence in HER2+ BCa pts. Here, we present the initial safety data. Methods: HLA-A2/A3+ BCa pts with stage I-III HER2+ disease at high risk for recurrence (pts not achieving complete response after Tz-containing neoadjuvant therapy or those undergoing up-front surgery with any node-positive disease if ER/PR- or ≥4 positive nodes if ER/PR+) were enrolled after SOC surgery, radiation and neo-adjuvant/adjuvant chemotherapy with approved Tz-containing regimen. Pts were randomized to receive Tz and NeuVax in the vaccine group (VG) or Tz and GM-CSF only in the control group (CG). Pts received vaccinations of NeuVax or GM-CSF intradermally every 3 weeks for 6 total vaccinations (primary vaccine series, PVS) starting with the third dose of Tz maintenance therapy. Starting 6 months after the completion of the PVS, pts received four booster inoculations, one every 6 months. Cardiac ejection fraction (EF) was assessed by either echo or MUGA at baseline and serially during treatment. Demographic and safety data were collected and analyzed. Safety analysis was initiated after enrollment of the 50th patient. Results: To date, we have enrolled 50 pts (VG n=22, CG n=28). There were no significant clinicopathologic differences between groups. There were no related grade 4 or 5 toxicities and no differences in related toxicities between the VG and CG (Grade 1: 96% vs 98.5%; Grade 2: 3.2% vs 1.5%; Grade 3: 0.8% vs 0%, p=0.14). There was no significant reduction in EF pre- to post-treatment in either group (VG: 61.1±5.4% vs 60.1±4.8%, p=0.55; CG: 62.3±5.7% vs 61.9±4.0%, p=0.74) and there was no difference in change between groups (p=0.54). Conclusion: The combination of Tz and Neuvax in HER2+ BCa pts is well tolerated and the cardiac effects from Tz are not worsened by the addition of NeuVax. We will continue to enroll up to our goal of 100 pts in this ongoing trial, and will report immunologic and clinical outcomes in the planned primary analysis after 24-months follow-up. Citation Format: Kaitlin M. Peace, Jennifer K. Litton, Rashmi Murthy, Timothy J. Vreeland, Diane F. Hale, Doreen O. Jackson, John S. Berry, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, George E. Peoples, Elizabeth A. Mittendorf. Pre-specified interim analysis in a prospective, randomized phase II trial of trastuzumab vs trastuzumab + NeuVax to prevent breast cancer recurrence in HER2+ breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT162. doi:10.1158/1538-7445.AM2017-CT162

Abstract B007: Improved disease-free survival in endometrial and ovarian cancer patients with low folate binding protein expression after treatment with the E39 peptide vaccine in a Phase I/IIa trial

Introduction: One of the most encouraging examples of targeted therapy for cancer is trastuzumab, but its success is dependent on levels of expression of its target, HER2. We have found that HER2 expression levels also have a significant impact on the efficacy of HER2-directed peptide vaccines. Analogous to HER2 in breast cancer, Folate Binding Protein (FBP) is over-expressed on ovarian and endometrial cancer cells (up to 80 - 90-fold higher) and increased FBP expression is associated with aggressive disease. As a result, multiple FBP-directed therapies are being developed. We are investigating E39 + GM-CSF, which is an HLA-A2-restricted FBP-derived peptide vaccine used to prevent recurrence in disease-free endometrial and ovarian cancer patients (pts) after standard of care (SOC), multi-modality therapy. We have shown that E39 is safe, effectively generates E39-specific immune responses, and may improve DFS when optimally dosed in a phase I/IIa trial.1 Little is known about the effects of FBP expression levels on FBP-directed therapies, including our E39 vaccine. Purpose: Here, we report clinical outcomes of patients based on FBP expression levels from a phase I/IIa trial of the E39+GM-CSF vaccine given for the prevention of recurrence in disease-free endometrial and ovarian cancer patients. Methods: Disease-free, HLA-A2+ pts were vaccinated (VG), while HLA-A2- pts were followed as untreated controls (CG). The VG received 6 monthly inoculations of E39+GM-CSF, including either 100, 500, or 1000mcg of peptide and 250mcg of GM-CSF. FBP expression testing was performed by immunohistochemistry and the results were graded 0-4+ based on the percentage of positively staining cells. Patient9s tumors were then categorized as low expression (FBPlo) if scored 0-1+ or high expression (FBPhi) if 2-4+. The pts were monitored for evidence of clinical recurrence through the SOC follow-up by their treating oncology team. Demographics, FBP expression and disease-free survival (DFS) were analyzed using appropriate statistical tests. Results: Thirty-eight enrolled pts underwent FBP expression testing (CG n = 20; VG n = 18). There were no clinicopathologic differences between groups (p≥0.1). Nineteen pts were found to be FBPlo (CG, n = 11; VG, n = 8) and 19 were FBPhi (CG, n = 9; VG, n = 10). Median follow up was 16.3 months. There was no significant difference in overall DFS between the CG and the VG (34.6% vs. 34.6%, p = 0.208). In FBPlo pts, there was improved DFS in the VG vs. CG (85.7% vs. 17.5%, p = 0.01) while there was no such difference in FBPhi pts (VG:13.9% vs. CG:44.4%, p = 0.83). Though groups were small, there was a dose-dependent effect on DFS; pts receiving 1000mcg (n = 4) had improved DFS compared to the Conclusion: This phase I/IIa trial has previously demonstrated that E39 is well-tolerated, elicits a strong, dose-dependent in vivo immune response and may improve DFS when properly dosed. This focused analysis based on FBP expression level revealed a DFS benefit in FBPlo, but not FBPhi, endometrial and ovarian cancer pts treated with E39. This may be due to immunotolerance from significantly higher endogenous exposure to the FBP antigen. This is concordant with findings in our trials of HER2-directed peptide vaccines in breast cancer pts. These findings warrant further study as they may have important implications regarding the target population for future E39 peptide vaccine trials. 1. Jackson DO, et al. Interim analysis of a phase I/IIa trial assessing E39+GM-CSF, a folate binding protein vaccine, to prevent recurrence in ovarian and endometrial cancer patients. In Press. Citation Format: Kaitlin M. Peace, Diane F. Hale, Timothy J. Vreeland, Doreen O. Jackson, Julia M. Greene, John S. Berry, IV, Alfred F. Trappey, Garth S. Herbert, Guy T. Clifton, Mark O. Hardin, Kathleen M. Darcy, Chad A. Hamilton, G. Larry Maxwell, George E. Peoples. Improved disease-free survival in endometrial and ovarian cancer patients with low folate binding protein expression after treatment with the E39 peptide vaccine in a Phase I/IIa trial [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B007.