An alphavirus-based therapeutic cancer vaccine: from design to clinical trial

TPS5104 Background: There is a strong rationale to combine therapeutic cancer vaccines with hormonal abrogation in prostate cancer. Androgen abrogation augments T-cell trafficking to prostate, decreases immune tolerance, increases production of naïve thymic T-cells, enhances cytotoxic T-cell repertoire. PSA TRICOM (PROSTVAC) is a therapeutic, viral-vector based, off-the-shelf, cancer vaccine of PSA & 3 co-stimulatory molecules in phase III testing. This was developed at the NCI in collaboration with Bavarian Nordic Immunotherapeutics. It has demonstrated safety and survival benefit in a randomized phase 2 trial of metastatic castrate resistant prostate cancer (mCRPC). Enzalutamide is a modern androgen receptor inhibitor (ARI) approved for the treatment of mCRPC. Data from the clinical trials with these therapies suggest good individual tolerability without any overlapping toxicities. Analysis of previous trials suggests that vaccines may enhance clinical outcomes with ARI. These data form the scientific basis for a combination approach of a cancer vaccine with ARI to control tumor progression in mCRPC. Methods: A randomized, phase 2, open-label clinical trial at the NCI will enroll 72 chemo-naïve, minimally symptomatic patients with mCRPC. They will be randomized (1:1) to enzalutamide (160 mg daily) alone, or enzalutamide with PSA TRICOM for treatment until radiographic progression. PSA-TRICOM will be administered in a core phase (with day 1, 15 and 29 then 4 additional monthly boosts) followed by continued boosts every 3 months. The primary end point will evaluate time to progression in each arm with secondary endpoints including overall survival and systemic immune responses (lymphocyte subsets, regulatory T-cells, regulatory T-cell function, cytokines, naïve thymic emigrants). If a therapeutic cancer vaccine can enhance the clinical efficacy of a hormonal agent such as enzalutamide, it may help define a new role for vaccines as an adjuvant to standard therapies. We will also evaluate this combination in a second trial in non-metastatic, castration-sensitive patients where this combination may yield its greatest clinical impact.

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A phase I/IIa clinical trial investigating the therapeutic cancer vaccine UV1 in combination with ipilimumab in patients with malignant melanoma: Four-year survival update.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.62 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 62-62

Author(s):

Espen Basmo Ellingsen ◽

Elin Aamdal ◽

Else Marit Inderberg ◽

Wenche Rasch ◽

Paal Brunsvig ◽

...

Keyword(s):

Clinical Trial ◽

Immune Responses ◽

Phase I ◽

Metastatic Melanoma ◽

Cancer Vaccine ◽

Complete Response ◽

Therapeutic Cancer Vaccine ◽

Gm Csf ◽

Clinical Responses ◽

Almost All

62 Background: Combining checkpoint blockade with a cancer vaccine may induce broader immune responses, leading to better clinical outcomes. UV1 targets the enzyme telomerase (hTERT) which is expressed in almost all cancer types and is essential for the immortality of cancer cells and a hallmark of cancer. UV1 consists of three synthetic long peptides and vaccination induces Th1 responses in most patients irrespective of HLA type. This trial explores the synergistic effect of CTLA-4 blockade and hTERT vaccination, allowing unchecked expansion of hTERT-specific T cell clones. Increased number of tumor-specific T cells is associated with a favorable clinical outcome in patients with metastatic melanoma. We investigated the safety, immunological and clinical responses of UV1 vaccine and ipilimumab in this group of patients. Methods: In a phase I/IIa, single-center trial (NCT02275416) patients with metastatic melanoma received treatment with UV1 (300 µg) + GM-CSF (75 µg) as an adjuvant, combined with ipilimumab (3 mg/kg). Safety was assessed according to CTCAE v. 4.0, and tumor responses according to RECIST v.1.1. Immune responses against UV1 peptides were monitored in peripheral mononuclear blood cells by using 3H-thymidine proliferation and IFN-γ ELISPOT assays. Tumor mutational burden (TMB) estimations were based on whole-exome sequencing. Results: 12 patients were treated from Feb to Nov 2015. Treatment was generally well tolerated. Adverse events mainly included injection site reactions and diarrhea. Immune responses occurred very early and 10/11 evaluable patients showed an immune response. Three patients obtained a partial response, and one patient a complete response. 3-year overall survival (OS) was 67%. 4-year survival outcome will be presented along with baseline characteristics and TMB estimations. Conclusions: Combining UV1 and ipilimumab is safe and induces clinical responses in melanoma. The high proportion of immunological responders and early induction of detectable immune responses suggest synergism. OS compares favorably to historical controls. Clinical trial information: NCT02275416.

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An alternative clinical trial design for early cancer vaccine development to phase 3+3 design.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2578 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2578-2578

Author(s):

Emily Gammoh ◽

Osama E. Rahma ◽

Richard Simon ◽

Samir Khleif

Keyword(s):

Clinical Trial ◽

Immune Response ◽

Early Development ◽

Phase Ii ◽

Cancer Vaccine ◽

Dose Escalation ◽

Cancer Vaccines ◽

Therapeutic Cancer Vaccine ◽

Alternative Design ◽

Immune Modulator

2578 Background: Traditional phase I, “3+3 dose escalation” design, is conducted to identify the MTD and in some cases the optimal biologic dose. Given their unique mechanism of action and the profile of their clinical outcome, this design may not apply to cancer vaccines. The therapeutic cancer vaccine FDA guidance calls for an alternative early development design. Nevertheless, whether an alternative design should be based on “dose escalation” is still an opened question. Methods: We analyzed the toxicity profile in 241 phase 1, 1/2 and pilot therapeutic cancer vaccine trials conducted between 1990 and 2011. Results: Sixty-two grade 3/4 vaccine related systemic toxicities were reported in 4952 treated patients (1.25 events/100 patients). Interestingly, only 2 out of 127 trials that used dose escalation reported vaccine related DLTs, both trials used bacterial vectors. Furthermore, correlation of immunological response with dose level showed no consistent trend. Conclusions: Our analysis suggests that in cancer vaccines neither toxicity nor cellular immune response correlates with dose levels. Accordingly, dose escalation is not suitable for most cancer vaccine studies. Here, we propose a two-step alternative design for early development of cancer vaccines. The first step is to determine and confirm the minimum Immune-Active Dose (IAD). If a vaccine class has been used in humans, IAD dose is chosen based on previous experience if the class is non-toxic (eg. Peptide), otherwise, a traditional dose escalation will be used. For a vaccine class that has not been tested or has undetermined toxicity we recommend “One Patient Escalation Design” (OPSD): one patient is treated per tested dose until an immune response is induced. To confirm this activity, an expanded cohort of 7 patients will be tested until demonstrating an additional response. This will then be used in phase II combination therapy trial. Alternatively, IAD can be directly tested in combination with an immune modulator in a phase II clinical trial using a two-stage design. The first stage of the phase 2 trial can be set at 4-5 patients for a target response rate of over 50%. If no response is seen, then the immune modulator will be escalated in the second stage.

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A Novel Combined Conjugate Therapeutic Cancer Vaccine, Recombinant EGF-CRM197, in Patients With Advanced Solid Tumors: A Phase I Clinical Study

Frontiers in Oncology ◽

10.3389/fonc.2021.745699 ◽

2021 ◽

Vol 11 ◽

Author(s):

An-Wen Xiong ◽

Jue-Min Fang ◽

Sheng-Xiang Ren ◽

Wei Li ◽

Jing Wang ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trial ◽

Cancer Patients ◽

Solid Tumors ◽

Cancer Vaccine ◽

Adverse Reactions ◽

Advanced Solid Tumors ◽

Vaccine Recombinant ◽

Therapeutic Cancer Vaccine ◽

Lung Cancer Patients

IntroductionThe therapeutic cancer vaccine recombinant Epidermal Growth Factor (EGF)-CRM197 is a novel combined conjugate EGF with CRM197 as a carrier protein. Immunization with the EGF-CRM197 vaccine can induce high levels of neutralizing anti-EGF antibodies that inhibit EGF/EGFR signaling and thereby suppress growth of tumors that rely on this signaling pathway. Herein, we characterize the humoral immune responses elicited by the recombinant EGF-CRM197 vaccine in patients with advanced solid tumors in a phase I clinical trial and assess the safety, tolerability, and immunogenicity of this vaccine (CTR20190473).MethodsA total of 16 subjects were enrolled in this study. Under 6 + 3 design, patients in each dosing cohort were administrated subcutaneously at a dosage of 0.4 mg, 0.8 mg, and 1.6 mg, respectively. The patients received vaccinations for immune induction (once a week for 4 consecutive weeks) and booster vaccinations (once every 4 weeks). Safety evaluation was performed 1 week after the immune induction. Booster vaccination was given until the occurrence of disease progression, intolerance, withdrawal of informed consent by the patient, or negative result of anti-EGF test after two booster vaccinations.ResultsVaccination with EGF-CRM197 is safe and well-tolerated in patients with advanced solid tumors. Adverse reactions at the injection site were the most common adverse events (AEs) in recipients. No severe adverse reactions post vaccination were observed in the present study. Vaccinated patients developed a robust neutralizing antibody response triggered by EGF-CRM197 that significantly reduced the levels of EGF in serum. For lung cancer patients who were super good antibody responders (sGAR) to EGF-CRM197, the median progress-free survival (PFS) was 4.83 months, significantly longer than that of the good antibody responder (GAR) patients with lung cancer whose median PFS was 2.10 months (P=0.0018). The median overall survival (OS) of GAR lung cancer patients was 10.67 months while the OS) for sGAR lung cancer patients was not reached until analysis was performed. The median follow-up of the sGAR lung cancer patients was 14.6 months.ConclusionOur study demonstrates that the recombinant EGF-CRM197 therapeutic cancer vaccine can induce a good immune response in patients with advanced solid tumors and is safe and well tolerated, which ensures further clinical development of the vaccine for extending the survival time of EGF-CRM197 sensitive patients with advanced solid tumors.Clinical Trial Registrationhttp://www.chinadrugtrials.org.cn, identifier CTR20190473, EGF-CRM197.

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