Lessons Learned From Other Immune Interventions
Despite all of these efforts, many of the hurdles facing cancer vaccines still persist. Thus, it has been of tremendous importance to scientists in the field that other immune interventions tested during the past decade or so showed convincing proof of clinical efficacy including objective and durable tumor responses in metastatic cancer. While such approaches demonstrated, in principle, the potency of the immune response to cancer, they also facilitated the characterization of the major obstacles, at the cellular and molecular level, interfering with the effectiveness of cancer vaccination.
Checkpoint Blockade Inhibition Unleashes the Host's Natural Immunity Against Cancer
The utilization of immune checkpoint blocking agents represented a major advancement in medicine leading to the first licensed therapeutic in this class, the CTLA-4 blocking antibody ipilimumab (Yervoy®) by Bristol-Myers Squibb.[44] This immune intervention, which blocks the T-cell inhibitory effects of CTLA-4 and unleashes the full potential of preexisting tumor antigen-specific T cells in some patients, showed an extremely durable tumor regression in metastatic melanoma and other tumor types.[45] This finding illustrates the fact that a subset of melanoma patients (15–25%) and other solid tumors can mount a potentially effective immune response against cancer that is kept in check primarily by CTLA-4 or PD-1. In addition, more recent data suggests that this antibody also has the capability to deplete Treg cells within the tumor stroma[46] raising questions in regard to its main mechanism of action. However, as most of the patients do not show a clinical benefit on treatment with this antibody alone, it is reasonable to hypothesize that they either do not elicit similarly capable tumor-specific immune effector cells or other checkpoint molecules are interfering with the resident T-cell activity. The former hypothesis is under investigation in clinical trials combining vaccination with CTLA-4 blockade.[42] The second hypothesis is currently being tested through the advancement of other checkpoint blocking agents such as anti-PD-1 antibodies, which already have shown promising clinical responses in various tumor types such as melanoma, RCC and lung cancer.[47,48] While this is an extraordinarily exciting progress in immunotherapy and medicine in general, it is important to underline that targeting one inhibiting molecule at a time is not a panacea considering the molecular heterogeneity of the immunological landscape in patients with cancer. This is undoubtedly reflected in the fact that a majority of patients treated with CTLA-4 or PD-1 blocking agents alone do not show a measurable clinical benefit. This is not surprising, taking into account that other checkpoint molecules and inhibiting mechanisms are functioning simultaneously in patients who are refractory to existing therapies.[49]
Modulation of the Tumor Microenvironment Enhances the Host's Immunity Against Cancer
Another line of work yielding promising results targets the tumor stroma, interfering with local inhibiting mechanisms, to revitalize the local immunity. Preclinical and clinical studies in hepatocellular carcinoma and melanoma, with tumor oncolytic viruses targeted to the tumor microenvironment showed not only a local effect but also an effective systemic deployment of immune mechanisms that could impact remote lesions.[50,51] Direct intra-lymph node administration of CpG adjuvant in follicular lymphoma also resulted in a successful deployment of a systemic immune response that was associated with systemic tumor regression in a subset of patients.[52] This autovaccination concept builds on the principle of utilizing the reservoir of endogenous tumor antigens, in combination with exogenous danger motifs, to adequately prime an active antitumor response. The importance of tumor stroma manipulation is supported by the results with other immune-modulating interventions such as anti-CD40 agonistic antibodies,[53] combinatorial approaches with chemotherapy leading to the release of antigen in context of coadministration of immune enhancers (the concept of 'immunogenic death'[54]), and the evidence of indirect mechanism of action through stromal collapse afforded by adoptive T-cell therapy (ACT) with IL-12-expressing T cells.[55]
Altogether, this evidence highlights that the tumor stroma has an active role and can be either a hurdle or a facilitator for cancer vaccines depending on its status or concomitant therapies.
Radical Restoration of a Functional Immune Repertoire Through ACT Results in Tumor Regression
Undoubtedly the most dramatic evidence to date of the power of cancer immunotherapy has been demonstrated by ACT, an approach pioneered at the Surgery Branch of the National Cancer Institute. This achieves a radical metamorphosis of the immune repertoire by first purging multiple immune-inhibiting mechanisms through preparative lymphodepletion.[56] Retrieval and ex vivo expansion of specific T cells isolated from blood or tumors (TILs) restores and amplifies the activity of preexisting antitumor T cells that then operate at maximum effectiveness on reinfusion into patients. The infused T cells, assisted by subsequent administration of immune-enhancing cytokines (such as IL-2), can mediate objective responses in a large majority of patients with metastatic melanoma. In some cases, complete regression of large tumors, coupled with extremely durable clinical responses (>5 years) representing possible functional cures were observed.[57] This tantalizing evidence, now reproduced in multiple independent centers,[58–61] has been largely limited to melanoma. It is quite possible but remains to be formally proven that the durability of the response is due to the elimination of cancer cells that have the ability to initiate a relapse process and are more likely to carry some antigenic somatic mutations.[62,63] The involvement or recruitment of other synergistic immune effector mechanisms, antigens or epitopes is also possible as it has been shown that different and functionally complementary T-cell subsets can exert an antitumor effect.[64]
The presence and antitumor effectiveness of TILs on ACT in certain cancers or patients represents a fundamental observation with far-reaching theoretical and practical implications. TILs emergence in a cancer patient, in the context of tumor progression, reflects the fact that immune-inhibiting mechanisms develop early on and operate by restricting TIL activity within the tumor, rather than preventing induction of immune responses. On the other hand, in different circumstances, a scarcity of TILs exhibiting antitumor capability indicates a different sequence of events. This involves a more rapid onset of immune inhibitory mechanisms that interfere, upstream, with priming of antitumor antigen effector cells. Alternatively, this could be due to a scarcity of immunogenic epitopes associated with the cancerous process. This stark dichotomy represented in Table 1 indicates that there could be a different way to classify cancers which can have practical consequences in terms of differential applicability of ACT, vaccination and immune checkpoint blockade. Being based on functional criteria consisting of the presence or absence of preexisting and potentially effective anticancer immune cells, this categorization, while distinct, is nevertheless compatible with the immune score categorization that utilizes histopathological descriptors.[65] A late breaking publication contrasting the high frequency of tumor-reactive TILs from melanoma lesions with the extremely low (0–3%) frequency of tumor reactive TILs from gastrointestinal cancers, lends strong support to this classification in Table 1 .[66]
Nevertheless, many cancers are devoid of a preexisting antitumor immune repertoire and are instead associated with central and peripheral immune tolerance against tumor antigens. Thus, a distinct strategy comprising T-cell receptor (TCR) or chimeric antigen receptor (CAR)-engineered T cells isolated from blood has been successfully utilized in the clinic to induce objective immune responses in a range of cancers such as melanoma, sarcoma, leukemia and lymphoma.[67–71] A more prolonged engraftment of an artificial repertoire borne by T cells could be achieved through engineered hematopoietic stem cells.[72]
There are three key aspects associated with this radical type of immune intervention that have considerable implications in designing next-generation vaccines and immunotherapies in general. First, infusion of tumor-specific T cells with optimal target affinity can lead to objective tumor responses only when preexisting immune-inhibitory mechanisms are disabled, for example, by chemotherapy or radiation preconditioning.[73] Second, methods to activate, amplify and maintain the infused, genetically engineered T cells are necessary and consist in the utilization of cytokines, engineering of costimulatory endodomains,[74] or utilization of booster vaccines (as discussed below). Third, downstream mechanisms responsible for the inactivation of the immune response are still operational and range from T-cell functional deviation,[75] immune exhaustion through acquisition of inhibitory molecules,[76] to immune escape by target antigen loss.[77] It is, thus, not surprising that additional approaches aimed at preempting these hurdles, such as checkpoint blockade, are being tested together with ACT [Ribas et al., Unpublished Data].
This area of research and development utilizing ACT is rapidly growing since it carries the promise of fully tapping into the potential of the immune system toward achieving objective clinical benefit in treated patients.
Important Mechanistic & Translational Information Can Be Generated by Understanding Autoimmunity
With much progress in autoimmunity and cancer immunology research during the past two decades, it has become evident that cancer immunotherapy has much to learn from the understanding of immunopathology of autoimmune disorders. It is known, for example, that adoptive transfer of autoreactive T cells in preclinical models does not merely result in autoimmunity, despite the capability of the T cells to proliferate in vivo or lyse target cells in vitro.[78] The contact with endogenous antigen onto normal tissue, or draining lymph nodes in this case, leads to an initial expansion followed by a contraction and anergy of the residual autoimmune cells without measurable evidence of autoimmunity. This is probably due to the plethora of immune checkpoint mechanisms that are also operational in cancer. In certain circumstances, these immune inhibiting mechanisms can be overcome by robust vaccination. For example, the utilization of a live vector expressing the target self-antigen in conjunction with ACT in a preclinical model of diabetes resulted not only in additional expansion, activation and persistence of autoreactive T cells in vivo but also in overt autoimmunity manifestation through target organ destruction.[78] This line of experimentation most significantly illustrates how T-cell repertoire provision in conjunction with vaccination could break tolerance and elicit tissue destructive autoimmunity even in organisms without known defects of immune homeostasis. This line of evidence could effectively bridge up the field of autoimmunity and cancer immunotherapy.
Altogether, this extensive body of scientific progress warrants a reconsideration of how therapeutic vaccination is positioned as an effective weapon against cancer. Some concrete options for vaccine repositioning are discussed below.
Expert Rev Vaccines. 2013;12(10):1219-1234. © 2013 Expert Reviews Ltd.
