In our last Discoveries article, we introduced the idea that the way a cancer treatment kills or damages a tumor can result in a marshaling of the immune system’s activity against the tumor and beyond, namely the metastases that account for the bulk of cancer’s deadly reputation. Whereas some forms of cell death suppress the immune system, other forms actually turn that system on, making it easier to eliminate a malignant disease.
Which treatment modalities are capable of inducing this so-called “immunogenic cell death” or ICD in tumors as a key part of cancer immunotherapy? The effect was originally seen with some radiation treatments in 1953, and later on was demonstrated with low-dose chemotherapy.
The understanding of ICD has revolutionized the view on the development of new anticancer therapies. Of course, finding treatments that are minimally toxic and do not result in treatment resistance (as is the case with chemo and radiation) is of paramount importance.
ICD is defined or determined in terms of various immune system responses as well as changes that can be seen at the microscopic level. One set of essential changes was described in the previous article—the production of damage-associated molecular patterns or DAMPs.
These so-called danger signals danger signals are passively exposed by cancer cells undergoing certain types of cell death. So once again, as a tumor is damaged, the immune system gets turned on to “mop up” other clusters of cancer in other parts of the body.
Recently, immunologists from Charles University in Prague, Czech Republic, teamed up with cell biologists from the Cell Death Research and Therapy Unit at the University of Leuven in Belgium to review four treatments that can help induce ICD. They published their evaluation of these immunogenic treatments online in the 7 January 2015 issue of Oncoimmunology.
The five treatments were: Photodynamic Therapy (PDT), ultraviolet C light, hyperthermia, high hydrostatic pressure, and ionizing radiation. All five of these modalities have been shown to elicit effective antitumor immunity. The authors discuss the evidence showing that ICD is induced by these modalities in cancer patients, along with their application in immunotherapy and, in particular, for creating anticancer vaccines. Given our website’s interest in PDT, we will focus here only on the authors’ coverage of that modality.
Photoimmune Therapy with Hypericin
Over the last two decade, PDT has become recognized as a promising treatment option due to its relative specificity as well as the absence of harmful side effects. A key attribute of PDT is that it can damage a particular subcellular site within the cancer cell. For example, Hypericin-PDT (using Hypericin from the herb, St. John’s Wort, as a photosensitizer) tends to target the membrane of a part of the cell called the endoplasmic reticulum, which leads to the release of danger signals that turn on the immune system. In addition to targeting tumors, PDT recruits various immune cells, such as dendritic cells or neutrophils, to the tumor. PDT triggers a few different types of ICD in cancer cells depending on the photosensitizer and light dose.
“Since early work in 1970s, there have been over 200 clinical trials involving PDT alone or in combination with other treatment modalities of various cancers,” the Belgian-Czech team notes. They go on to point out that local tumor PDT can enhance whole-body tumor-specific immune responses in cancer patients, as well as being able to induce effects on distant metasteases or tumors that were not part of the original treatment.
The authors decribe studies that demonstrate how Hypericin-PDT induces ICD in humans and laboratory animals. According to their assessment, Hypericin-PDT is the most effective inducer of oxidative stress in the endoplasmic reticulum among all the known ICD inducers. (The authors do not, however, provide data showing comparisons with other superb and extensively studied chlorin-based photosensitizers, such as Bremachlorin and Laserphyrin.)
Hypericin-PDT causes the release of four key DAMPs and produces all the major immune-related hallmarks of ICD. One major effect is to cause the maturation of dendritic cells. These fully mature dendritic cells signal the effective proliferation of key immun esytems such as the interferon-producting T-helper and T-killer lymphocytes.
For this reason, Hypercicin-PDT can result in “tumor rejection” as well as in the creation of therapeutic vaccines. The use of vaccines in conjunction with PDT is an example of what we call Photoimmune Therapy.
The Future of Photoimmune Therapy
PDT’s ability to destroy a tumor along with mustering concomitant help of the immune system to mount a full-fledged attack on metastases or distant tumors is an attractive therapeutic aim. One way this photoimmune objective can be further realized is by using PDT to generate vaccines that are specific for tumors, vaccines that also contain DAMPs for added cancer-curbing power.
“PDT, in general, has been shown to be suitable for vaccine generation,” the Belgian-Czech team states, “as immunization with PDT-killed tumor cells or cell lysate induces strong antitumor immunity in mice….” They add that these benefits can be attained in the absence of any additional immune-stimulating substances.
Moreover, the authors state, “photoimmunotherapy with dendritic cells loaded with PDT-treated tumor cells has been shown to stimulate the cytotoxicity of T and NK cells toward tumors in mice, suggesting its clinical potential… Physical cell death-inducing modalities like PDT…have been proven to be able to act as in situ vaccines, and to aid in inducing antitumor immunity in human patients…most likely via ICD induction. ”
But despite some proven clinical success in using PDT as cancer treatment, clinical trial data on the use of PDT-based cancer vaccines in immunotherapy are virtually non-existent. Even so, PDT, hyperthermia and other modalities mentioned in this report appear to have great potential for the development of new whole cell-based or dendritic-based vaccines. This remains an area in urgent need of research attention.
Adkins I, Fucikova J, Garg AD, Agostinis P, Špíšek R. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology. 2015 Jan 7;3(12):e968434. eCollection 2014.