How Can Cytoreduction Surgery Improve the Prospects for Cancer Patients Receiving Immunotherapy?

KEYWORDS::

• cancer
• immunotherapy
• surgery

Cancer, the leading cause of death for people under the age of 85 years in the USA, claims over 1500 lives per day [1,2]. The four most common cancers (lung, colorectal, prostate and breast cancer) account for more than half of total cancer incidences in the USA [2]. The most common cancer therapies are surgery, chemotherapy and radiation [2]. Except for a few chemotherapeutic regimens, surgery is the only definitive treatment available. Unfortunately, surgery has a 40–60% recurrence rate depending on the type of cancer [2]. This high recurrence rate has led to the combination of surgery with traditional therapies such as chemotherapy, immunotherapy and radiation.

Immunotherapy utilizes the body‘s own immune system to target cancer cells. Almost a century ago, it was hypothesized that a tumor can be recognized as foreign by the host and thus the immune system can be effective in eliminating these foreign cells [3]. Since then, the cancer immune response has been confirmed in knockout mice [4] and the exact phases of this mechanism, termed immunoediting, are still being rigorously studied [5].

Immunotherapy is advantageous because of its low toxicity, tumor specificity and ability to potentially produce long-term immunity. Immunotherapy seeks to eliminate cancer through both active and passive approaches [6]. Active immunotherapy utilizes our knowledge of tumor antigen expression and exploits endogenous, immunological processes of T-cell induction to eliminate the tumor [7]. Regardless of the modality, the primary goal of active immunotherapy is to prime and induce antigen-specific T-cell responses in order to eradicate residual disease and prevent postoperative recurrences. On the other hand, passive immunotherapy involves the use of immunologically active agents that are capable of exerting anti-tumor effects independently from the host‘s immune system [7]. Such passive approaches include adoptive T-cell transfer techniques, which involve ex vivo amplification and reintroduction of autologous cytokine-induced killer or lymphokine-activated killer cells [7]. Various mechanisms by which immunotherapy reduces tumor burden have been elucidated, including increased intratumoral neutrophils, enhanced CD8 T-cell trafficking and decreased vasculature of the tumor [8,9].

Our group and others have found that immunotherapy can be highly effective [8–11]. However, in both animal studies and human trials, with increasing tumor burden, immunotherapy loses its potency [9,12]. In fact, immunotherapy is most effective for states of minimal disease [9]. This finding has led us to further investigate the synergistic combination of cytoreduction surgery and immunotherapy. Our research has led us to believe that combining surgery and immunotherapy will lead to improved patient outcomes.

Our preclinical studies in addition to clinical trial data indicate that anti-tumor responses such as antigen-specific CD8 T cells are still produced in patients with a large tumor burden [9,12,13]. However, immunotherapy is ineffective in treating large tumors, suggesting that some aspect of the advanced tumor microenvironment is preventing the CD8 T cells and other anti-tumor responses of the immune system from reaching their full anticancer potential [10,14]. Possible mechanisms include: systemic immunosuppression, decreased intratumoral vascularity [8], rapid tumor growth kinetics, and tumor-associated immunosuppression such as myeloid-derived suppressor cells [10,11]. It has been shown that as a tumor advances, a complex array of immunosuppressive factors expand and reduce the efficacy of endogenous anti-tumor immune responses [15]. Perhaps, most important is immunosuppression in the tumor microenvironment caused by inhibitory molecules, such as CTLA-4 [16] and PD-1, and immune cells, such as CD4⁺Foxp3⁺ T-regulatory cells [17], M2 tumor-associated macrophages [18], and N2 tumor-associated neutrophils [19]. Additionally, in the tumor microenvironment are tumor- and stromal-derived factors, such as TGF-β [15], VEGF, arginase [20], IL-10 and prostaglandins, which further suppress anti-tumor immune responses. These immunosuppressive molecules, cells and factors partly explain the lack of success of immunotherapy in curing advanced tumor burden.

Given the correlation of immunosuppression with disease burden, immunotherapy has theoretical benefits when used in a state of ‘minimal disease‘ (i.e., after patients have had cytoreduction by surgery, chemotherapy and/or radiation) [9]. Several years ago our group made the observation that neoadjuvant (preoperative) immunotherapy (in the form of Ad.IFNβ) was effective in treating very large mesothelioma tumors when therapy was followed by a complete surgical removal [12]. These findings were reproduced by Grinshtein and colleagues who also demonstrated increased immunotherapy efficacy when combined with surgery in a neoadjuvant setting [21]. Recently, we have shown that reduction of tumor enhanced two intratumoral immunotherapy strategies inhibiting non-metastatic and metastatic murine lung cancer growth [10]. The two intratumoral immunotherapies that are currently being evaluated in clinical trials are: adenoviral vector encoding herpes simplex thymidine (AdV-tk) [22] and an adenoviral vector delivering the gene for IFN-α (Ad.IFNα) [23]. Furthermore, we have shown that this beneficial effect of partial resection may be due to decreased myeloid-derived suppressor cells. Our partial resection model mimics the ‘debulking‘ surgery used for difficult thoracic cancers such as malignant mesothelioma and the residual tumor from surgery that can lead to recurrence.

As suggested from our recent experience, intratumoral immunotherapy (or in situ vaccination) may provide significant benefits. In brief, this approach consists of delivering immune stimulants directly into the tumor to generate a cell-mediated immune response. This response can neutralize the tumor locally, while also generating a systemic response that can traffic to distant metastatic foci. In addition to generating an immune response with a broad array of tumor-associated antigens, intratumoral immunotherapy has multiple logistical advantages. Intratumoral injections are efficient in that they do not require ex vivo manipulation. This approach has the potential to exploit the benefits of whole-tumor vaccines without the limitations of these vaccines, which include invasive and potentially dangerous procedures to harvest tumor. Furthermore, patients with accessible tumors typically have the most tumor burden, and are thus least likely to benefit from whole-tumor vaccines [24]. Due to the initial local nature of this therapy, there are also fewer side effects than systemic injection of immune-activating cytokines. Finally, this ‘one-size-fits-all‘ approach is economically more feasible because once the therapy is developed, it can be used for a variety of tumor types.

Although the combination of surgery and immunotherapy is appealing in principle, this approach has a significant challenge in that surgery itself may actually suppress the anti-tumor immune response. Many studies suggest that surgery generates a transient immunosuppression that allows increased tumor growth [25,26]. This window is thought to result from inflammatory, neural and hormonal factors. One aspect of this immunosuppression stems from general anesthesia, which has a role in decreasing NK cell activity. The other aspect, surgery itself, impairs production of IL-2 and generates immune suppressor cells. With this in mind, the ideal combination of surgery and immunotherapy may require both an immunostimulating and immunosuppressive agent. The immunostimulating agent will activate an anti-tumor response whereas the immunosuppressive agent will act against specific cytokines and regulatory cells, which prevent the immune response.

While this approach holds much promise, unfortunately, the medical community has been unable to replicate the preclinical success with immunotherapy and surgery in humans. One proposed reason is that the current animal models used are insufficient [27]. Many animal models focus on primary tumor and do not incorporate a surgical component, which may influence the immune system in a complex manner, or use mice with compromised immune systems. For example, the study of human cancer in immune-compromised (i.e., severe combined immunodeficiency or nude) or transgenic mice does not replicate the immune response seen in human patients. The optimal animal model should utilize an immunocompetent host given the complex inflammatory and immune responses that occur during the perioperative period, such as the presence of an endogenous anti-tumor immune response (concomitant immunity), perioperative immunosuppression and inflammatory consequences associated with wounds and wound healing.

In conclusion, both preclinical and clinical data indicate that immunotherapy can be successful in eliminating residual disease [10,12,21]. Surgery still remains the most effective therapy of cancer and cures approximately 50% of all patients, however, the remaining half of cancer patients succumb to recurrent disease [28]. Immunotherapy could potentially eliminate the residual tumor cells and micrometastatic disease through potent immune cells, which can traffic to and kill specific tumor cells. The precise formula for clinical immunotherapeutic success with surgery has yet to be elucidated. However, there are various aspects of immunotherapy that are yet to be agreed upon, including: timing of immunotherapy in relation to surgery, combination of immunosuppressive and immunostimulating agents, and an adequate animal model. Future studies combining preoperative intratumoral immunotherapy, followed by cytoreduction and then another round of immunotherapy may be the key to success to curing advanced cancers in the future.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.