Effects of Hyperthermia on the Immune System
It has been known for decades that hyperthermia has several important effects on the functioning of the immune system (Table).[12-14] Indeed, fever-range hyperthermia (39°-41°C) is thought to represent an evolutionary adaptation that has helped humans combat a wide range of infectious and immunologic attacks. One of the principal mediators of the immune effects seen with hyperthermia is the HSP family mentioned above. Because HSPs are molecular chaperones, in a cancer-bearing patient they are expected at any given time to contain a sampling of the intracellular proteins currently being transcribed by cancer cells. HSPs are released from dying cancer cells that have been treated with heat in combination with chemotherapy and/or radiotherapy. These HSPs contain tumor-related antigens, abnormal proteins that are produced by cancer cells and recognized as foreign material by the immune system. Dendritic cells and other antigen-presenting cells exposed to the HSPs are not only exposed to the tumor antigens carried by the HSPs but they are also activated—since HSPs are interpreted as a danger signal. The activation of dendritic cells with HSP-derived tumor antigens allows for the cross-priming activation of CD8+ cytotoxic T cells against these antigens, thereby triggering an acquired anti-tumor immune reponse. Hyperthermia thus serves as a method of HSP-mediated auto-vaccination against the tumor.
In addition to improving the presentation of tumor antigen to T cells, hyperthermia also enhances leukocyte trafficking; this is an important effect, since lymphocytes must not only be activated against an antigen but must also be able to make their way to the tumor in order to attack it. Heat improves leukocyte trafficking by increasing Inter-Cellular Adhesion Molecule 1 (ICAM-1) expression on lymphoid high-endothelial venules and by enhancing the expression of L-selectin on lymphocytes.[18,19] This combination of influences allows T cells to stick to the lymphatic endothelium and migrate selectively into peripheral lymph nodes, thereby resulting in the accumulation of tumor-recognizing T cells at a site where they can have useful anti-tumor effects.[20,21] Hyperthermia also increases chemokine release in the vicinity of the tumor, enabling lymphocytes to selectively home to the appropriate site of action.[22,23]
Lastly, hyperthermia also activates the innate immune system. Natural killer (NK) cells in particular are a cell type that has been shown to be strongly influenced by hyperthermia.[24,25] Heat leads to clustering of antigen receptors (NKG2D) on the surface of the NK cell and to the expression of MICA on tumor cells, both of which lead to NK targeting of tumor cells. In summary, heat activates both the acquired and innate branches of the immune system.
Hyperthermia as an Adjuvant to Radiation and Chemotherapy
Although cells in S phase have been observed to show a response to hyperthermia, cells in this phase are less susceptible to the effects of radiotherapy. However, a synergistic effect is noted when heat is combined with radiotherapy and thermal radiosensitization in cancer cells increases, a phenomenon that is especially apparent in cells in S phase. It has been shown in vitro that heat obstructs the repair mechanism for radiation-damaged DNA via inhibition of DNA-polymerases α and β. The sequence of treatments is also quite important, with heat preceding radiation producing the greatest therapeutic ratio.
Hyperthermia has also been noted to enhance the cytotoxicity of several chemotherapeutic agents.[28,29] The drug-heat interaction is best illustrated by a thermal enhancement ratio (TER). The TER as it relates to thermal chemosensitization is the ratio of cells that survive at a given temperature to those that survive at 37°C per chemotherapeutic agent used. Several ways of characterizing the drug-heat interaction have developed; these include “additive,” “threshold-activity,” and “independent.” Most alkylating agents (eg, cyclophosphamide(Drug information on cyclophosphamide), ifosfamide(Drug information on ifosfamide)) and DNA cross-linking agents (eg, mitomycin(Drug information on mitomycin) C [MMC]) are observed to be more cytotoxic when combined with heat (“additive” drug-heat interaction).[30,31] DNA intercalators (eg, doxorubicin(Drug information on doxorubicin)) demonstrate threshold-like behavior: little to no additional cytotoxicity is noted below a certain temperature, but beyond a threshold temperature an additive effect is observed. For the most part, antimetabolites (eg, fluorouracil(Drug information on fluorouracil)) demonstrate no improved effect when combined with hyperthermia and thus are characterized as “independent”. The temporal relationship between the administration of hyperthermia and chemotherapy varies according to the drug given. With some drugs (eg, cyclophosphamide and gemcitabine(Drug information on gemcitabine) [Gemzar]), maximal cytotoxicity is observed when they are given prior to hyperthermia, while others (eg, etoposide(Drug information on etoposide)) work best when given during heat application. One might assume that the hyperemia associated with hyperthermia would enhance drug delivery to tumor cells, but the pharmacokinetics and fidelity of the drugs themselves may also be affected. As the delivery mechanisms of hyperthermia advance, so will the study of thermal pharmacodynamics.
Thermal dosimetry (thermometry) is critical to the optimization of hyperthermia treatment as well as to the minimization of potential heat-related toxicity. Although delivery standardization is difficult to implement because of varying target locations and clinical circumstances, Oleson and colleagues created the concept of the “thermal isoeffect dose,” which is used to quantitate a given thermal dose as “equivalent heating minutes” at 43°C.[35,36] Each additional 1°C doubles the equivalent number of minutes at 43°C. Each 1°C below 43°C effectively decreases the 43°C-equivalent time-dose by a factor of 4. Tissue temperature has typically been recorded via invasive intratumoral thermistors or by a catheter placed in a hollow viscus (eg, the urethra, bladder, or rectum).[38,39]
Although dosimetry has advantages with regard to the evaluation of treatment temperature and the ability to modify the therapy dose as needed, the possible effects of thermal shielding, direct complications from probe placement, and patient discomfort must also be considered. Thus, other experimental models of thermal dosimetry measurement have been proposed. Recent investigation into the use of magnetic resonance (MR) imaging–based thermometry has proved very promising. MR–temperature distribution mapping is a combined measurement of perfusion and tissue temperature. Intratumoral perfusion can also be affected by hyperthermia, and this, too, can be imaged with MR.[42,43] Additionally, consideration has been given to the use of imaging-based thermometry techniques in conjunction with contrast-containing liposomes for hyperthermia-mediated drug delivery.
Hyperthermia as a Treatment for Bladder Cancer
Although the concept of hyperthermia to treat malignancy has existed for many years, efforts to further its use had waned because of the technical limitations of tissue delivery. However, there has been renewed interest of late in the realm of urologic tumors, especially with regard to using hyperthermia to treat prostate and urothelial carcinomas. Urothelial carcinoma (UC) of the bladder is the fourth most common solid tumor in American men; although it has a widely variable pathologic presentation, 75% of patients present with non–muscle-invasive bladder cancer (NMIBC). The biology of UC is just as varied, with high-grade NMIBC progressing to invasive disease in a substantial number of cases.
Intravesical bacillus Calmette-Guérin (BCG) immunotherapy is commonly used as a first-line therapy to help prevent the progression of NMIBC to a muscle-invasive phenotype. When BCG therapy fails, it is a common practice for patients to consider radical cystectomy, an aggressive extirpative surgery associated with many side effects. In an effort to reduce the number of patients having to suffer the morbidity of radical cystectomy, alternative therapies are actively being sought. Additionally, many patients with low-grade NMIBC have recurrent tumors that may not be a threat to their life but that certainly can dramatically impair their quality of life. Patients with multi-recurrent disease are typically treated with intravesical BCG therapy, although other intravesical chemotherapies are also used. When these treatments fail and the tumors continue to recur, having alternative therapies available would be beneficial.
The additive effect of combining hyperthermia with chemotherapy has been validated in vitro several times.[32,45] For example, van der Heijden and colleagues demonstrated that MMC combined with hyperthermia induced incremental cytotoxicity in multiple human bladder cancer cell lines. The following year, the same group from the Netherlands compared the effect of several chemotherapy agents used in combination with heat. Synergism was demonstrated with MMC and with epirubicin(Drug information on epirubicin), and to a lesser extent with gemcitabine. Animal studies have confirmed these data.
These preclinical studies have led to human trials, and many patients with bladder cancer have been treated with hyperthermia, usually in combination with intravesical therapy. The most commonly used regimen is hyperthermia combined with 40 mg of intravesical MMC. Several studies using this approach have been published, although many of these studies unfortunately involve the same core group of investigators.[46,49-60]
Several conclusions can be derived from these studies. First, hyperthermia increases the absorption of MMC (although not to a level associated with myelosuppression), indicating that heat improves the penetrance of MMC across the bladder wall. This effect suggests that heat helps deliver more MMC to the tumor, especially tumor hiding deeper in the bladder where it may be on the verge of progressing to muscle invasion.
Second, while hyperthermia does modestly increase treatment toxicity, it does not result in life-threatening events or the inability to complete therapy.[46,55,61] In fact, virtually all of the side effects of combination MMC and hyperthermia are mild and temporary and require minimal, if any, treatment.
Third, combination hyperthermia and MMC is better than MMC alone at preventing recurrences of NMIBC. This was best demonstrated in a randomized trial in which the NMIBC recurrence rate was 4.8 times higher in the MMC arm than in the MMC plus heat arm. An earlier randomized trial showed similar results, and together these studies demonstrate that MMC administered with heat is superior to MMC alone for preventing NMIBC recurrences.
Fourth, when compared to historical controls treated with MMC alone, combination MMC and hyperthermia appears to reduce the risk of progression of NMIBC to muscle-invasive disease. This conclusion is based on a progression rate of approximately 8% in patients treated with hyperthermia and MMC, compared with a historical rate of about 15% to 20% for MMC alone[62,63]—although the underlying progression risk in these populations may not be the same, making it difficult to draw firm conclusions.
Fifth, while patients in whom BCG immunotherapy has previously failed are generally considered to be at high risk for treatment failure, combination MMC and hyperthermia probably salvages more of these patients than MMC alone.[55,61] Sixth, the clinical response to combination MMC and hyperthermia can be long-lasting, with many patients (40% to 50%) remaining disease free at 3 to 5 years post-treatment.[59-61] Lastly, although the data in bladder cancer patients are sparse and definitive conclusions are difficult to draw, hyperthermia may also be combined with systemic chemotherapy and/or radiation therapy in patients with muscle-invasive bladder cancer, with the potential effect of improving treatment efficacy and/or providing a bladder-sparing result.[64,65] This type of strategy has been shown to be effective in other tumors, such as sarcoma, cervical cancer, breast cancer, and rectal cancer.
Modern technologies have changed our ability to accurately deliver and measure the dose of deep pelvic hyperthermia and have consequently sparked a renewed interest in using this therapeutic modality to treat bladder cancer. Trials are ongoing at our institution and others to further delineate who benefits from hyperthermia and how its delivery can be optimized.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.