Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

A novel quantitative flow cytometric method for measuring glucocorticoid receptor (GR) in cell lines: Correlation with the biochemical determination of GR

Journal URL: http://www.sciencedirect.com/science/journal/0022175

Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence.

3097 Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development. Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide+GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6. Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9±5 days (d) and is similar in vDUR/cDUR (p = 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ± 8.8 d (no difference in vDUR/cDUR [p = 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p = 0.34; R6- p=0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p=0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p=0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p=0.09). Relative risk for developing DUR for LR &gt; 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p=0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p=0.05). Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here. Clinical trial information: NCT00524277. </jats:p

Abstract CT209: Correlation of robust local reactions prompting GM-CSF dose reduction to clinical response in a phase II trial of the AE37+GM-CSF HER2 peptide vaccine

Abstract Background: We are conducting a phase II clinical trial of the HER2 peptide vaccine AE37+GM-CSF for prevention of breast cancer recurrence in disease-free, node-positive or high-risk node-negative patients (pts), who have completed standard of care therapy. AE37, an Ii-Key hybrid of the HER2-derived peptide AE36 (aa:776-790), is an MHC Class II epitope capable of stimulating tumor reactive CD4+ helper T-cells. Previous investigation of intradermal inoculation with E75 (HER2 aa:369-377) +GM-CSF vaccine in phase I/II trials showed no recurrences at 24 months among the 18% of pts requiring a GM-CSF dose reduction due to robust local reactions (LR). Phase I/II studies have shown the safety, immunogenicity, and potential clinical benefit of AE37 + GM-CSF. Here, we examine the relationship between GM-CSF dose reduction and clinical recurrence rate (RR) in pts receiving AE37+GM-CSF. Methods: Patients with any level of HER2 expression (IHC1-3+) were enrolled and randomized to receive 6 monthly intradermal inoculations of AE37+GM-CSF or GM-CSF alone (controls) during the primary vaccination series, then four booster vaccinations administered every 6 months. Enrollment has been completed and pts continue with their vaccination series. LRs are measured after each inoculation, and pts with a LR measuring ≥ 100 × 100mm have their GM-CSF dose reduced on subsequent inoculations. Local and systemic toxicity are being monitored and clinical recurrences documented. Proportional RR are compared using a chi-square or Fisher exact test as appropriate. Results: Of 301 enrolled pts, 154 were randomized to the vaccinated arm (VG) and 147 randomized to the control arm (CG). The groups are well-matched for clinicopathologic characteristics. Toxicities have been almost exclusively grade 1 and 2. Study-wide, 18.9% of pts required dose reduction (CG 15.6%, VG 22.1%; p = 0.19). In vaccinated pts, the RR in the dose reduced group (DR) was 5.9% (2/34) versus the non-dose reduced group (NDR) RR of 14.2% (17/120) (p = 0.25). Among controls, the DR RR was 17.4% (4/23) vs the NDR RR of 12.9% (16/124) (p = 0.74). Comparing all DR pts, the relative risk of recurrence was reduced by 66% in the VG DR compared to the CG DR (5.9% versus 17.4%; p = 0.21). Conclusions: In a randomized phase II trial of the AE37+GM-CSF vaccine, pts who required a dose reduction of GM-CSF due to robust LR trend toward a lower recurrence rate. The overall dose reduction rate is similar to that in E75 trials (18.9% vs 17.9%) and occurred more frequently in the VG than CG. While dose reduction is seen in both the VG and the CG, the clinical benefit is only seen in the VG suggesting that while the LR may be a result of the GM-CSF, the specificity provided by the peptide is required for clinical benefit. Furthermore, these data suggest that GM-CSF should be dosed to produce large LR to enhance the benefit of peptide vaccines in the adjuvant setting. Citation Format: Julia M. Greene, Erika J. Schneble, Jennifer K. Litton, Jonathon Martin, Alfred F. Trappey, John S. Berry, Timothy J. Vreeland, Diane F. Hale, Guy T. Clifton, Alexandros Ardavannis, Michael Papamichail, Sonia Perez, Sathibalan Ponniah, Elizabeth A. Mittendorf, George E. Peoples. Correlation of robust local reactions prompting GM-CSF dose reduction to clinical response in a phase II trial of the AE37+GM-CSF HER2 peptide vaccine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT209. doi:10.1158/1538-7445.AM2015-CT209</jats:p

An assessment of disease features and immune response in breast cancer patients that did not recur after receiving HER2 peptide, AE37 vaccine in a randomized phase II trial.

625 Background: In a phase I trial of AE37, the Ii-Key hybrid of HER2 derived peptide AE36 (776-790), administered with immunoadjuvant GMCSF demonstrated the vaccine to be safe and capable of stimulating CD4+helper T cells with HER2 specific anti-tumor activity. Here we present analysis of immune markers and patient feature that may impact recurrence from an ongoing prospective, randomized, single-blinded Phase IIb trial of AE37+GMCSF v GMCSF alone in adjuvant high risk breast cancer (BC) patients. Methods: After completion of standard therapy; disease-free, node positive or high risk node negative BC patients (pts) were randomized to receive either AE37+GMCSF or GMCSF in 6 monthly intradermal inoculations. Immunologic responses were measured using [3H]-thymidine incorporation assay (in vitro), delayed-type hypersensitivity (DTH) reactions (in vivo) and T regulatory cells (Tregs). Among those vaccinated recurrent pts (VR) are compared to non recurrent (VNR) pts. Results: We have vaccinated 109 pts with 8.3% recurrence rate at 2 year median follow up. VR v VNR were younger (44 v 50 yo p=0.11), had higher grade (67% v 44% p=0.32), more ER/PR- (44% v 38% p=0.75), larger tumors (89% v 50% p=0.06), and node positive (89% v 70% p=0.37). No difference for HER2 status (IHC 3+, 44% v 49% p=0.64). Both VR and VNR responded to vaccine though the mean DTH and proliferative stimulation index was approximately 10% less in VR pts (18 v 20 p=0.73; 1.96 v 2.2 p=0.77 respectively). The most predictive measure was change in Tregs with VR pts less likely to decrease their Tregs levels (50% v 76% p=0.17) after vacination and more likely experience increased Tregs (17% v 8% p=0.48). A decrease in Tregs had an inverse trend towards recurrence (p=0.17). Conclusions: Preliminarily, it appears most pts immunologically respond to vaccine though slightly less for VR in most assays. The changes of Tregs appear to correlate best with disease recurrence. Whether this reflects an association with disease status or a failure of the vaccine is yet to be seen. These levels may become important in predicting risk for clinical recurrence in future vaccine trials. </jats:p