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Shubham Pant, MD, MBBS Vaccines are a major topic of interest in the world of cancer care, offering the promise of an effective treatment option in traditionally hard-to-manage tumor types that can potentially be personalized for individual patients. In order to further elucidate the current role of vaccines in the therapeutic paradigm of multiple tumor types and learn more about promising vaccines in development, OncLive ® interviewed several investigators to gain their perspective on these exciting agents. “Vaccines are truly coming to the forefront of cancer treatment,” Shubham Pant, MD, MBBS, said in an interview with OncLive .
“One extreme are vaccines for [patients with] melanoma [where] the cancer is very susceptible to [treatment with] a vaccine. What I am interested in is looking at vaccines in earlier settings. For example, in early-stage pancreatic cancer, even after resection and adjuvant treatment, patients still have a high chance of [disease recurrence].
We are trying to develop vaccines that target micrometastatic disease [in order to] delay recurrence and/or [contribute to] a higher cure rate.” Pant is a professor in the Department of Gastrointestinal (GI) Medical Oncology with a joint appointment in the Department of Investigational Cancer Therapeutics (Phase I Center) at The University of Texas MD Anderson Cancer Center in Houston. Perhaps the most well-known cancer vaccine is BCG, which is comprised of an attenuated strain of Mycobacterium bovis and was originally developed as a tuberculosis vaccine.
1 After showing preclinical efficacy, it was evaluated in multiple cancer types before eventually earning FDA approval in 1990 for the treatment of patients with non–muscle-invasive bladder cancer (NMIBC). BCG was the first immunotherapy to gain FDA approval and remains a standard of care in NMIBC. For patients with NMIBC who experience disease progression following BCG treatment, nadofaragene firadenovec-vncg (Adstiladrin) represents an FDA-approved treatment option.
In December 2022, the agent became the first FDA-approved adenoviral vector-based gene therapy when it gained an indication for adult patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ with or without papillary tumors. 2 At the time of the approval, data from the phase 3 study CS-003 (NCT02773849), which supported the regulatory decision, demonstrated that response-evaluable patients who received the agent (n = 98) experienced a complete response (CR) rate of 51% (95% CI, 41%-61%) and a median duration of response (DOR) of 9.7 months (range, 3 to 52+).
Nadofaragene firadenovec is now being examined in patients with intermediate-risk NMIBC in the ongoing phase 3b ABLE-32 trial (NCT06510374). 3 “Nadofaragene firadenovec has an intravesical application,” Neal D. Shore, MD, FACS, medical director of the Carolina Urologic Research Center in Myrtle Beach, South Carolina, explained in an interview with OncLive .
“We have [many] other intravesical applications, but this therapy combines interferon alfa-2b with an adenoviral component. It’s a viral gene vector [therapy], and ultimately, the mechanism of action is to stimulate the patient’s interferon production, which [makes it an effective] apoptotic agent [against] urothelial carcinoma.” Neal D.
Shore, MD, FACS In April 2010, another cancer vaccine, sipuleucel-T (Provenge), was approved by the FDA for the treatment of patients with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). 4 Sipuleucel-T induces an immune response to prostate cancer cells by targeting the prostate cancer tissue antigen prostate acid phosphatase (PAP) and generating PAP-specific T cells which recognize and kill PAP-expressing prostate cancer cells. In the melanoma space, the oncolytic virus-based vaccine talimogene laherparepvec (T-VEC; Imlygic) is approved by the FDA for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery.
5 T-VEC is comprised of a genetically modified herpes simplex virus type 1 which replicates within tumor cells to produce granulocyte-macrophage colony-stimulating factor (GM-CSF), which eventually leads to cancer cell death. The agent was approved by the FDA in October 2015 after data from the phase 3 OPTiM study (NCT00769704) demonstrated that the agent was significantly superior to GM-CSF in patients with unresectable advanced melanoma in terms of inducing a durable response ( P <.0001).
Several cancer vaccines are currently being studied in clinical trials in disease areas including pancreatic, colorectal, prostate, and lung cancers. In the phase 1 AMPLIFY-201 trial (NCT04853017), the investigational KRAS-targeted cancer vaccine ELI-002 is being examined in patients with pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer (CRC) who underwent successful surgical resection and had KRAS G12D– and G12R–mutated disease. 6 Data from AMPLIFY-201 showed that evaluable patients who received the 2-peptide formulation of ELI-002 (n = 25) experienced a median overall survival (OS) of 28.
9 months and a median relapse-free survival (RFS) of 16.3 months. The median RFS for patients with PDAC (n = 20) and CRC (n = 5) was 15.
3 months and 16.3 months, respectively. The median OS was 28.
9 months in the PDAC group and not reached (NR) in the CRC group. “[Vaccines] could have a [large] impact in patients with resected disease and potentially in patients with high-risk disease,” Pant noted. “They could work well for a majority of patients with pancreatic cancer because most of these patients have high-risk disease by definition.
When we can kill the micrometastatic disease, that’s where we can have the maximum impact because we’re moving towards curing these patients, which might not have been achievable before.” A 7-peptide formulation of ELI-002 designed to target mutations in KRAS G12D, G12R, G12V, G12C, G12A, G12S, and G13D is being examined in the phase 2 AMPLIFY-7P study (NCT05726864) for the treatment of patients with KRAS / NRAS -mutated solid tumors; data from an interim analysis of the study is expected in the first half of 2025. Another novel cancer vaccine, aglatimagene besadenovec (CAN-2409), is being evaluated in multiple clinical trials, including the phase 3 PrTK03 study (NCT01436968).
7 Aglatimagene besadenovec is an off-the-shelf, replication-defective adenovirus which delivers the herpes simplex virus thymidine kinase gene to a specific tumor to induce an individualized immune response. In December 2024, Candel Therapeutics announced that PrTK03, which examined aglatimagene besadenovec plus the prodrug valacyclovir (Valtrex) and standard of care (SOC) external beam radiation vs SOC in patients with newly diagnosed intermediate- to high-risk localized prostate cancer, met its primary end point of disease-free survival (DFS). At a median follow-up of 50.
3 months (95% CI, 45.37-51.29), patients in the intention-to-treat population who received aglatimagene besadenovec (n = 496) experienced a 30% reduction in the risk of disease recurrence or death compared with those in the SOC arm (n = 249; HR, 0.
70; 95% CI, 0.52-0.94; P = .
0155). 8 A 14.5% relative improvement in DFS in favor of the investigational arm was reported at 54 months.
7 Additionally, the 2-year pathological complete response (pCR) rates were 80.4% and 63.6%, respectively ( P = .
0015). 7,8 Glen Gejerman, MD, MBA “The potential clinical impact [of these findings] is substantial,” Glen Gejerman, MD, MBA, the codirector of Urologic Oncology at Hackensack Meridian Health in New Jersey, and a principal investigator of the phase 3 study, said in a statement to OncLive . “There hasn’t been any new treatment or significant change in the standard of care for localized, nonmetastatic prostate cancer for over 20 years.
If approved, CAN-2409 could transform the treatment paradigm, offering patients with localized disease an effective option that may significantly reduce the risk of disease recurrence and limit the need for salvage therapies that significantly reduce quality of life.” Aglatimagene besadenovec is also being evaluated in combination with valacyclovir or acyclovir and SOC immune checkpoint inhibitor (ICI) therapy in stage III or IV non–small cell lung cancer (NSCLC) and with valacyclovir or acyclovir and SOC chemoradiation in borderline resectable PDAC in the phase 2 LuTK02 (NCT04495153) and PaTK02 studies (NCT02446093), respectively. 9,10 Data from LuTK02 demonstrated that patients with advanced NSCLC who had an inadequate response to ICI treatment who received aglatimagene besadenovec (n = 46) achieved a median OS of 24.
5 months. 9 Additionally, patients who experienced disease progression after ICI treatment (n = 41) experienced a median OS of 21.5 months.
Findings from the final OS analysis of PaTK02 showed that patients in the aglatimagene besadenovec arm (n = 7) experienced a median OS of 31.4 months compared with 12.5 months among those treated with SOC alone (n = 6).
10 The 24-month OS rates were 71.4% and 16.7%, respectively.
In April 2023, the FDA granted fast track designation to aglatimagene besadenovec plus valacyclovir and pembrolizumab (Keytruda) for the treatment of patients with stage III or IV NSCLC who are resistant to frontline PD-1/PD-L1 inhibitor therapy and who do not have activating molecular driver mutations or experienced disease progression on directed molecular therapy. 11 In December 2023, aglatimagene besadenovec plus valacyclovir was granted fast track designation by the FDA in PDAC. 12 mRNA-based cancer vaccines are also being developed in a variety of tumor types, including mRNA-4157 (V940).
13 mRNA-4157 is an individualized neoantigen therapy that contains a synthetic mRNA which codes for up to 34 neoantigens. The agent is designed and produced based on the mutational signature and DNA sequence of a patient’s tumor. In the phase 2 KEYNOTE-942 trial (NCT03897881), patients with resected stage IIIB to IV cutaneous melanoma who received mRNA-4157 in combination with pembrolizumab (n = 107) achieved a median RFS of NR compared with 42.
51 months (95% CI, 16.59-not estimable) among those who received pembrolizumab alone (n = 50; HR, 0.510; 95% CI, 0.
288-0.906; P = .019).
14 The 30-month RFS rates were 74.8% and 55.6%, respectively.
Patients in the combination arm also experienced a significant distant metastasis-free survival benefit vs those in the monotherapy arm (HR, 0.384; 95% CI, 0.172-0.
858; P = .015). In October 2024, it was announced that Merck and Moderna had initiated the phase 3 INTerpath-009 trial (NCT06623422) evaluating mRNA-4157 plus pembrolizumab as adjuvant therapy in patients with resectable stage II to IIIB NSLSC who did not achieve a pCR with neoadjuvant pembrolizumab plus chemotherapy.
13 Additionally, the phase 3 INTerpath-001 (NCT05933577) and INTerpath-002 (NCT06077760) trials are examining mRNA-4157 in combination with pembrolizumab as adjuvant therapy in patients with resected high-risk stage IIB to IV melanoma and NSCLC, respectively. “The future of cancer vaccines looks incredibly promising. We’re witnessing an expansion of therapeutic approaches across multiple platforms, with growing evidence supporting their efficacy,” Gejerman said.
“We’re seeing a lot of exciting advancements within neoantigen vaccines that target unique tumor mutations, creative viral vector approaches, and novel combination strategies. The combination of cancer vaccines with other immunotherapies, such as checkpoint inhibitors or cell therapies, holds promise for treating [patients with] previously resistant cancers.”.
