Induction of antitumor responses by vaccines requires strong immunogens. Heterologous viral prime/boost immunization with the BN-CV301 vaccine promotes activation of immune responses that provide a clinical benefit to patients with cancer. This viral platform may be used to harbor different antigens and prime tumor immunity potentially useful for combinatorial strategies.
See related article by Gatti-Mays et al., p. 4933
In this issue of Clinical Cancer Research, Gatti-Mays and colleagues (1) report their results after testing safety of their BN-CV301 viral vaccine in a dose-escalation trial in patients with advanced solid malignancies. Characterization of T cells as a main antitumor mechanism has led to the development of a wide number of immunotherapies aimed at activating this cell subset, to specifically target tumor cells while leaving healthy cells unaffected. With the goal of activating antitumor T cells, the identification in the past 25 years of tumor antigens allowed the design of vaccines, strategy with a presumed direct and specific effect for tumor cell elimination (2). However, despite the great effort put in their development, with the exception of Provenge for prostate cancer, no therapeutic cancer vaccine has been approved. Several factors have been attributed to the limited effect of vaccines, some of them related to the vaccine itself, such as the poor immunogenicity of antigens included in the vaccine and the vaccine formulation. In addition, immunosuppressive elements present in the tumor microenvironment have been also considered as responsible for the poor vaccine efficacy.
In this work, Gatti-Mays and colleagues analyze their new BN-CV301 vaccine, obtained by modifying not only tumor antigens encoded by the immunogen, but also the formulation, in the way of a new combination of viral vectors. Original works by this group had reported immunogenicity and clinical activity of PANVAC (3), an earlier version of BN-CV301. PANVAC was based on a prime/boost combination of a recombinant vaccinia virus encoding MUC1 and CEA tumor antigens plus costimulatory molecules B7.1, ICAM-1, and LFA-3 (TRICOM), followed by a boost with a recombinant fowlpox virus encoding the same transgenes. Recombinant poxviruses are potent vectors for immunogenic purposes, because first, they have a high capacity to harbor large antigens, and second, as opposed to tumor cells, they carry all the elements considered as danger signals responsible for activating innate immunity and necessary to promote antigen presentation and T-cell priming. Indeed, some viral components trigger upregulation of the so-called signal 2 molecules as well as the release of cytokines important for T-cell activation. Vaccinia viruses have shown a remarkable capacity to trigger Toll-like receptor (TLR)-dependent and -independent inflammatory cytokine production and activation of adaptive immunity. However, in addition to these properties, the large genome of poxviruses also encodes genes responsible for disrupting TLR signaling. Identification and manipulation of these mechanisms has allowed the development of more potent vaccines. More importantly, in the case of PANVAC and BN-CV301, the presence of TRICOM transgenes results in an even higher costimulation and adhesion capacity by antigen-presenting cells. Thus, viral vectors have shown their potency in different settings, even when targeting tumor-associated antigens, considered in some cases as poorly immunogenic due to mechanisms of central tolerance. Generation of antibodies against the viral vectors is a consequence of their high immunogenicity. However, this problem has been solved by designing heterologous prime/boost strategies, avoiding thus the neutralization of the vaccine in subsequent administrations. Moreover, modulation of TLR signaling properties in vaccinia viruses used for immunotherapy has shifted immune responses from the humoral to the cellular arm. In addition to formulation (modulation of the vector and expression of antigens as transgenes), antigen immunogenicity can be further improved by sequence modification. Indeed, both CEA and MUC1 epitopes are modified to yield stronger T cells agonists, leading to epitopes with enhanced HLA binding and T-cell recognition. However, despite a measurable clinical activity of PANVAC, as indicated by authors, the replicative nature of vaccinia virus may raise potential safety issues, particularly in immunocompromised individuals and patients with atopic dermatitis. Accordingly, in the new BN-CV301 version, a nonreplicative modified vaccinia Ankara (MVA) virus encoding the same transgenes has been used as priming vector. MVA vectors, despite their attenuated nature, retain their TLR-dependent and -independent capacity to activate innate immunity, and different versions encoding a variety of antigens have been clinically tested without relevant safety issues (4). Accordingly, patients with cancer vaccinated with BN-CV301 have not shown serious adverse events, with temporary, self-limited 1/2 grade events, confirming vaccine safety. Interestingly, the MTD was not reached.
Together with this safety profile, an evident clinical activity induced by vaccination is reported, resulting in 1 patient with partial response and an important proportion of patients with stable disease, more manifest in those with mutated KRAS. This was accompanied by induction of T-cell responses in more than 90% of patients, directed against CEA and MUC1, which increased after boosting. An interesting aspect regarding vaccine-induced responses is the generation of T cells specific for antigens not included in the vaccine (e.g., brachyury). This “epitope-spreading” effect suggests an efficient elimination of tumor cells and the release of new tumor antigens for their presentation, allowing thus the generation of a wider repertoire of tumor-specific T cells and avoiding the appearance of escape mutants nontargeted by vaccine-encoded antigens.
As mentioned earlier, in addition to vaccine-related factors, tumor microenvironment may impair vaccine efficacy. In this sense, in the tumor, checkpoint inhibitors may modulate the activity of negative regulators affecting effector functions of T cells induced by the vaccine. Moreover, checkpoint inhibitors may also facilitate the initial priming of these cells. On the other side, vaccines are a straightforward strategy for T-cell activation and tumor inflammation. Therefore, vaccines such as BN-CV301 and checkpoint inhibitors arise as strategies providing mutual benefits when administered in combination. As indicated by Gatti-Mays and colleagues, a phase 1b trial combining BN-CV301 and PD-1 inhibitors is ongoing, and future results will tell us about the benefit provided by this combination. Meanwhile, in 2 of 3 patients treated with BN-CV301 plus PD-L1 blockade, a notable decrease in tumor markers and a prolonged period of stable disease has been observed, uncommon findings in patients with KRAS-mutant, MSS colorectal tumors treated with checkpoint inhibitors, as noted by the authors.
Although this type of viral vaccines shows a high immunogenicity, one has to be cautious when interpreting the results. Despite encouraging data in a previous randomized vaccination phase II clinical trial, a recent phase III trial in patients with prostate cancer evaluating PROSTVAC [a vaccine equivalent to PANVAC but expressing prostate-specific antigen (PSA) as tumor antigen], did not meet the overall survival (OS) primary endpoint (5). Factors regarding the number of patients recruited in the phase II trial for OS calculations and differences in OS in control groups in both trials have been proposed as responsible for the differences observed. Nevertheless, the use of the poxviral platform in the right context and in combination with checkpoint inhibitors, as proposed by the authors, may provide a meaningful clinical benefit.
Finally, in a similar way to that observed in the past after tumor antigen cloning and identification, the development of next-generation sequencing technologies is adding a new boost to the vaccine field. Sequencing of tumors is now affordable and identification of neoantigens (neoAg), new sequences arising from tumor mutations and recognized by T cells, is accessible in a timely manner. These technical advances and the identification of the role that neoAgs play in antitumor immunity have prompted the use of new vaccines encoding neoAgs (2). These vaccines have proven to be immunogenic in preclinical and clinical settings, with some examples also used in combination with checkpoint inhibitors. Although in most cases they have been formulated as synthetic peptides or mRNA molecules, they can be incorporated in any other formulation, such as the viral–vector combination reported by Gatti-Mays and colleagues, which has shown such a good safety and immunogenicity profile. Therefore, the vaccine platform reported in this issue could well represent a good example of a component of a potential combinatorial strategy that includes an optimized vaccine and checkpoint inhibitors (Fig. 1).
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
P. Sarobe is supported by grants from Instituto de Salud Carlos III cofinanced by European FEDER funds (PI17/00249), from Fundación Bancaria La Caixa "Hepacare" project, and received financial support from the "Murchante contra el cáncer" initiative.