Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide

Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide

Oncolytic viruses consist of a diverse range of DNA and RNA viruses traditionally thought to mediate their effects by exploiting aberrations in tumor pathways, allowing preferential viral replication in, and killing of, tumor cells. Their potential for anti-cancer therapy is based upon the concept that selective intratumoral replication will produce a potent anti-tumor effect and possibly bystander or remote cell killing, whilst minimizing normal tissue toxicity. A virus may manifest directly as a contagious disease with a clinical pathology of varying significance. Vaccination is the earliest form of immunotherapy, corresponding to the discovery of the immune system itself, and infectious disease vaccinations are perhaps the greatest advance in the history of medicine. Conventional chemotherapy does not result in high levels of penetration into tumors or lymph nodes. Furthermore, recent evidence indicates that intratumoral or intravenous injections of replicative oncolytic viruses such as herpes simplex-, pox-, parvo-, or adenoviruses may also reactivate the human immune system. In this review, we consider the use of histone deacetylase (HDAC) inhibitors as a means of boosting virus replication and lessening the negative impact of innate immunity on the direct oncolytic effect.

Moreover, several concepts using different virus preparations are now in clinical trials in humans and may proceed to a new treatment option. Of 146 uninjected non-visceral lesions, 60 (41.1 %) decreased in size by ≥ 30 %, the majority of which (44 [30.1 %]) completely resolved. Until recently, the therapeutic options in stage IV melanoma were very limited, mostly centered on dacarbazine used as monotherapy or in various combinations. The first approved oncolytic virus for clinical use in the world is to be used in conjunction with chemotherapy (Fluorouracil and cisplatin) for head and neck cancer. This provides a diverse set of activities that can be harnessed and manipulated. OVs are self-replicating and able to lyse tumor cells selectively while sparing normal cells. On account of these promising efficacy results, there are ongoing clinical trials with anti-CTLA-4 (ipilimumab, Bristol-Myers Squibb or tremelimumab) plus anti-PD1 or anti-PD-L1 in other tumor types such as renal cell carcinoma, NSCLC, small-cell lung, triple-negative breast, pancreatic, gastric, and bladder cancer [97].

CAR, chimeric antigen … The viral genome contains six genes: nucleoprotein (NP) phosphoprotein (P), matrix protein (M), fusion protein (F), hemagglutinin-neuraminidase (HN), and large protein (L). Reovirus, a naturally occurring, unmodified virus that has already completed significant clinical testing (as Reolysin), and has just entered phase 3 for head and neck cancer, can elicit antitumor immune activation.61 In some models, reoviral replication and direct oncolysis are not necessarily required for therapy,38 although the clinically relevant contribution of direct tumor killing and antitumor immune activation for any OV remains to be elucidated in patients. The antitumor immune effects of reovirus can be enhanced with the addition of interleukin-2 (IL-2),62 and are associated with adaptive priming against TAA in tumor-draining lymph nodes,61 illustrating that both innate and adaptive arms of the immune response can be exploited to improve therapy. And the reported hypophysitis rate of 8%, Ryder and colleagues observed, is probably an underrepresentation because clinical presentation is often nonspecific and indistinguishable from the constitutional symptoms of cancer. Eligible patients will have advanced nodal disease and be randomized to standard therapy with radiation plus cisplatin or the combination with OncoVEXGM-CSF . A range of genes has been incorporated into a number of viruses, although immuno-stimulatory modification of a virus does not inevitably enhance antitumor therapy.

Immunotherapy works to direct the extensive repertoire of the host immune system to fight cancer. Transfer of NK cells labeled with the NK specific marker DX5 from surgically stressed and no surgery control donors into naive recipient mice represents the first in vivo evidence that links surgery to the spread of cancers via NK cells (3). The agent’s developer emphasizes that activated Ras is the primary determinant of cancer cell infection, but recent evidence published in BMC Cancer last August suggests a more complicated picture. In the largest, most promising published clinical trials to date, oncolytic viruses have been injected directly into the tumor, to initiate both local and distant regression.64,67 Intratumoral delivery avoids the concern of virus neutralization by circulating antibodies () and suits the paradigm whereby the mere presence of a virus within a tumor can act as a “danger signal” to alert and activate the immune system.69 However, despite the acceptance of the intratumoral route used in the current phase 3 trial of Oncovex in melanoma, systemic intravenous delivery, if effective, is always likely to be more popular with clinicians. The findings of recent resistance monitoring initiatives indicate that HSV should remain sensitive to valacyclovir therapy, despite a long history of acyclovir usage Previous Section. The requirement of effective “stealth” mechanisms illustrates that virus-mediated cell killing can be a highly immunogenic way for cells to die. One of the exciting new strategies in immunotherapy is the adoptive T-cell therapy protocol developed by Rosenberg’s group at the National Cancer Institute wherein tumor infiltrating lymphocytes (TILs) are isolated and expanded ex vivo before reinfusion back into the patient.72,73 The successful application of this approach requires significant in vivo expansion of the infused cell product and this only occurs if the patient first undergoes chemotherapeutic or radiotherapeutic lymphodepletion.74,75 While the response rates with this approach are breathtaking (objective tumor responses in up to 70% of cases75) patients experience sometimes lethal virus reactivation and other side effects of cytotoxic chemotherapy that reduce patients’ quality of life.

Thunder and Lightning: Immunotherapy and Oncolytic Viruses Collide
Another strategy that not only targets tumor antigens, but also enhances T-cell expansion in cases where tumor antigens are weak or unidentified, investigators have developed multifunctional CARs (chimeric antigen receptors) that can be expressed as transgenes in T cells and redirect T cells to tumor antigens, regardless of their native T-cell receptor specificity. Among lesion responses (n = 85), the CR rate was 45%, and the PR rate was 8%, with SD in 31%. Each CAR is composed of single chain antibody variable regions that recognize whole antigens on a tumor cell surface, linked to the zeta ζ-chain of the T-cell receptor to trigger killing and to the intracellular endodomains of costimulatory molecules to trigger proliferation. Second, the high likelihood of tumor reduction in injected lesions could translate into palliation of symptoms, such as pain or bleeding, in superficial lesions which are readily accessible for direct injection. In clinical practice, this strategy has yet to be optimized to produce antitumor effects without toxicity. The concept was also valid for gene engineered fibroblasts expressing immunostimulatory genes and was used to induce anti-tumor immune responses [15]. Peripheral blood mononuclear cells (PBMCs) also secrete IFN-α, IFN-β and Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) after treatment with reovirus.

We redirected EBV-specific T cells to the disialoganglioside, GD2 expressed by neuroblastoma using a GD2-specific CAR. Additional modification of tumor cells with molecules that protect them from inhibitory ligands like transforming growth factor-β, may increase the potency of this approach.90 Importantly, this strategy should have little toxicity, and should not require cytotoxic lymphodepletion. Arrows indicate time of virus injection. If the OV-specific T cells were modified to express a tumor-specific CAR, then virotherapy could be consolidated with tumor directed T-cell infusions (see ). More recent clinical reports have described the regression of leukemia,22,23 Hodgkin’s disease,24,25 and Burkitt’s lymphoma26 concomitantly with measles infection. Curr Cancer Drug Targets 7: 157–167. 30, 36).

Oncolytic virus (OV)-specific T cells could be expanded ex vivo after the second vaccination. Perhaps because of its well-known susceptibility to immunotherapy, melanoma appears to be a particularly good target for oncolytic virotherapy, responding well not just to HSV-GMCSF (OncoVEX) but also to vaccinia virus therapy22. OVs may also provide a solution to the problem of tumor antigen-specific T-cell anergy. While stimulation of peripheral blood T cells with viral antigens to which the donor has been exposed can reactivate polyclonal CD4+ and CD8+ T cells with specificity for multiple HLA class I and II epitopes in multiple viral antigens, this is rarely true for T cells specific for nonviral “self” antigens, which are frequently tolerized during development and hence are weak and anergic to in vitro reactivation and expansion for use as T-cell therapy. While it is known that TILs have been successfully expanded from melanoma patients and retain their antitumor specificity, not all tumors have TILs and not all TILs can be successfully expanded in vitro. Enhanced reactivation of TA-specific T cells in patients who received an oncolytic adenovirus encoding human GM-CSF has been reported.47 This characteristic of OVs may be exploited by the transgenic expression of tumor-encoded antigens, so that OV may be used not only to eliminate tumors, but to facilitate the ex vivo reactivation and expansion of TA-specific T cells that could subsequently be gene modified and infused as described above and further induced to expand by additional OV treatment. Long-term immune control may arise from OV-infected tumor cells boosting both innate and subsequent adaptive tumor specific immune responses.

2006). A main theme in Dutch research on adenovirus vector development was directed at tumor targeting. Infection of melanoma cells with vaccinia virus could provide additional stimulation of antitumor immunity by introducing viral pattern recognition ligands in the vaccine. CDDP, i.v. This oncotropism results at least in part from the dependence of H-1PV on proliferation and differentiation factors that are dysregulated in neoplastic cells (20). Through this indirect systemic effect, the immune system contributes to the elimination of cancer cells, including those not directly targeted by the OV including those forming small disseminated metastases [9,22] (). Therefore, they might represent an innovative therapy for a wide range of applications and tumor types in both dogs and humans.

Of 400 baseline or new lesions, 306 were evaluable (i.e., had measurements at ≥ 2 visits), including 146 (47.7 %) uninjected non-visceral lesions and 32 (10.5 %) visceral lesions). Generation of an anti-tumour immune response has a complexity that starts with the recognition of tumour antigen with the help of HLA proteins by T cells. So what are the critical factors that lead to the impressive therapeutic outcomes observed by Bridle and colleagues. As the pharmacologic effects against host innate immunity wane, a large debris field of OVs and tumor antigens could be more promptly recognized by the antiviral host response leading to a secondary long-term vaccination effect responsible for effective tumor immunity (). Second, intravenous injection of the boosting vector is essential; intratumoral or subcutaneous VSV-DCT was ineffective. The significance of the 4-1BB pathway has been highlighted in numerous diseases, including cancer, and it has been previously shown that anti-4-1BB mAbs possess potent antitumor properties derived from their effectiveness in activating and protecting T and NK cells [123]. Other priming strategies are also effective with the oncolytic VSV-DCT boost suggesting that it may be effective with a number of vaccine platforms or perhaps in patients that have natural pre-existing anti-TAA immune responses that may just need a “jump-start”.

NDV-HUJ was found to facilitate the cleavage of Livin in advance melanoma cells.34 Abbreviations: NDV, Newcastle disease virus; HUJ, Hebrew University Jerusalem. Using OVs as vaccines to expand T cells which can be genetically modified with CAR, and protocols based on classic prime-boost immune priming are two examples in a field of united immune- and viral-therapies which is already blossoming in the laboratory. We believe that it is time to move toward more clinical testing of the ideas presented in this review, including extensive monitoring of the immune response against both virus and tumor in patients, to provide as much translational data as possible for continued iterative testing and optimization between laboratory and clinic.

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