Cancer Cryo-Immunotherapy: A Battle Between the Immune System and Cancer
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Haakon Ragde, MD The Haakon Ragde Foundation for Advanced Cancer Studies, Seattle, WA and
Duke K. Bahn, MD The Prostate Institute of America of Community Memorial Hospital, Ventura, CA
PCRI Insights February 2006 vol. 9, no. 1

As most of us know, the immune system plays a critical role in controlling and eliminating infectious organisms, including many bacteria and viruses. More controversial has been the question of whether the immune system can effectively control cancer growth and metastases. The last several years have provided new insights into how the immune system works, along with possible means to activate the system so that immune cells will recognize markers on cancer cells and destroy these cells. These advances have led to the emergence of a new and promising therapeutic strategy in cancer treatment, referred to as tumor immunotherapy, which can successfully treat and possibly cure selected patients.1,2

A potentially key weapon is the dendritic cell (DC), a scarce white blood cell that can now be generated by the millions in the laboratory, where they are cultured from precursor cells that circulate in the blood. Dendritic cells are the body’s scavengers, constantly prowling our bodies in an effort to communicate to the immune system the various biological goings-on in the cells throughout the body. In the case of disease states involving bacteria, virally infected cells, and cancer cells, distinct molecular markers, called antigens, reveal the problematic nature of these cells. Dendritic cells gobble up these cells and break them down into smaller protein fragments which they prominently display on their cell surfaces (Figure 1). The dendritic cells then migrate to the nearest lymph node, rather like detectives returning with evidence to the forensic lab at the local precinct station, in this case bringing biochemical evidence of disease with them.

Figure 1. Dendritic cells uptake antigens,process them, and display them on their surfaces.

In the lymph node, the dendritic cells present the biochemical evidence to lymphocytes known as “naïve T cells” (Figure 2). If the presented antigen is identified as “problematic” – i.e. related to infection or cancer – certain naïve T cells are capable of undergoing activation, wherein their numbers increase greatly. These activated T cells migrate out of the lymph node and search the body for cells bearing the same antigens and kill them (Figure 2). Among these T cells are the same type of killer T cells that will attack and unleash torrents of strikingly powerful substances in an attack that can completely destroy organs weighing several pounds (such as the kidney, liver, or heart) in mismatched human transplants.

Figure 2. Dendritic cells induce activation of T cells in the lymph node.

Strategies using dendritic cells to fight cancer (dendritic cell vaccination) have entered clinical testing in the past decade.3 Most of these methods administer patients’ own dendritic cells after first “arming” them with a synthetic cancer antigen in the laboratory. Patients’ T cells specific for the chosen cancer antigen are activated and can in theory kill cancer cells bearing the antigen (Figure 3). These studies have shown that dendritic cell injections were well tolerated with minimal side effects. Clinical responses were observed in approximately half of the trials.4

Figure 3. Scanning Electron Micrograph of a Killer T Cell Engaging a Tumor Cell.

An alternative strategy for dendritic cell vaccination is to introduce a patient’s dendritic cells into the cancerous tissue5, thus allowing these dendritic cells to acquire antigens directly from that patient’s own cancer cells (“intra-tumoral dendritic cell injection”). Since cancer is generally composed of a heterogeneous (highly variable) population of cancerous cells expressing numerous antigens, multiple cancer antigens can, in theory, be acquired by dendritic cells using this strategy. Vaccines that target multiple antigens may be a superior choice for eliciting a more complete immune response against cancer than those that target only one antigen.

 

Releasing Antigens from a Tumor

It has been speculated that an even more efficient means of obtaining the antigenic components of a cancerous mass in the body might involve first damaging the tumor – thereby causing it to release some or all of its antigens – and then introducing the dendritic cells into the damaged tumor environment. These dendritic cells may then be able to better acquire the tumor antigens (as in Figure 1) than if the tumor cells had not been damaged before the injection of the dendritic cells into the tumor mass.

This speculation has found support in several recently reported studies. For instance, when mice with implanted experimental tumors were treated with chemotherapy followed by injection of dendritic cells into the growing tumor, complete regression of these tumors was observed.6,7 No such regression was noted when the mice were treated with chemotherapy alone or dendritic cell injection alone. In these cases, chemotherapy hypothetically resulted in cellular death of part of the rapidly growing tumors.

Similar observations have been noted when the “damaging” treatment was hyperthermia (heat)8, radiation9, or cryotherapy10,11 of the tumor. In these cases, the mice that received the combination of the damaging therapy and the injection of dendritic cells into the damaged tumor fared significantly better – as measured by either the growth of the tumors, the number of new tumors, or the survival of the mice – than the mice that received the damaging treatment or dendritic cell injection alone.

Taken together, these observations suggest that there may be a therapeutic approach to human cancers that combines a tumor damaging strategy followed by the injection of autologous, or self-derived, dendritic cells into the treated tumor. An example of such an approach is a Stanford University clinical trial that damages liver tumors with thermotherapy (heat), followed by dendritic cell injection.5

 

Dendritic Cell-Based Cryo-Immunotherapy

In the spring of 2004, the Seattle-based Haakon Ragde Foundation partnered with Sangretech Biomedical, a Seattle biotech company, and the Prostate Institute of America in Ventura, California, to study a similar immunotherapeutic modality.12 This therapeutic approach entails the use of cryotherapy (freezing) of prostate tumors followed by intra-tumoral dendritic cell injection. This combination is known as “dendritic cell based cryo-immunotherapy.” In this case, tumor damage and antigen liberation is achieved via cryotreatment of the prostate and/or metastases. (See Figure 4.) An investigation of this combination in PC patients is currently underway at the Asian Hospital and Medical Center in Manila, the Philippines.

Figure 4. Dendritic Cell-Based Cryo-Immunotherapy.

The primary objective of this study is to explore the safety of a potential cancer treatment that first freezes the prostate, and follows with an injection of millions of the patient’s own dendritic cells into the gland. As stated above, this process may allow dendritic cells to capture tumor antigens released by the dying PC cells in response to the cryotherapy. As illustrated schematically in Figures 1 and 2, the process is designed to result in a system-wide immune assault upon remaining tumor cells that have spread – or may have spread – from the original, primary PC.

In contrast to other tumor-damaging approaches such as chemotherapy and radiation, cryotherapy may be a superior means of damaging the tumor and releasing tumor antigen. There is strong biological evidence to support this hypothesis: first, cryotherapy will not damage the immune system as chemotherapy and radiation do. Second, it is well established that immunotherapy works best with smaller tumor volumes, and cryo-destruction results in a swift reduction of most of the cancerous mass (along with a predictable release of antigen).

Seven PC patients have traveled to the Philippines to take part in this trial in 2005. Although additional clinical evidence will be necessary before any conclusions regarding Cryo-Immunotherapy’s safety and effectiveness may be reliably ascertained, early labs results (including PSA) in these seven patients are encouraging. Additional labs tests, imaging studies, and physical evaluations in the seven patients treated thus far are ongoing. Based on these early results, a U.S. trial, to take place at the Prostate Institute of America in Ventura, California, is in the planning stages. Studies are also being contemplated in other cancer types, as the technique is applicable in theory to most solid tumor cancer.

No significant toxicity issues related to dendritic cell administration have been encountered to date. Cryoablation of the prostate has led to some common and expected side effects, specifically some fatigue and some non-febrile sweating during the first 24-48 hours after treatment, though these were temporary. Overall, dendritic cell-based cryo-immunotherapy has been well tolerated by the first seven patients.

Therapeutic cancer vaccines are attractive because of their negligible side effects that allow patients to maintain their quality of life – a privilege rarely possible with conventional cancer treatments. As clinical responses to vaccine therapy continue to advance as a result of new knowledge and improved techniques, there will be an increasing use of this modality in the management of all solid cancers, both for clinically localized cancers and for cancers that have spread.

Editor’s Note: As the authors make clear, Dendritic cell-based Cryo-Immunotherapy is still in an early stage of testing, and significant time and effort is still required before conclusions can be reached. Since this article was written, the Manila-based cryo-immunotherapy trial has continued to recruit patients. Preparations are now underway for the planned U.S. trial at the Prostate Institute of America in Ventura, California. Further information about this investigational protocol is available from The Prostate Institute of America at 888-234-0005 or The Haakon Ragde Foundation for Advanced Cancer Studies at 206-273-7919.

References
1. Rosenberg, S.A., Development of effective immunotherapy for the treatment of patients with cancer. Journal of the American College of Surgeons, 2004. 198(5): p. 685-96.

2. Dudley, M.E., et al., Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science, 2002. 298(5594): p. 850-4.

3. Ridgway, D., The first 1000 dendritic cell vaccines.[see comment]. Cancer Investigation, 2003. 21(6): p. 873-86.

4. Ragde, H., Cavanagh, W., Tjoa, B.: Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer. Journal of Urology, 172:2532-2538, 2004.

5. Sponsors: Stanford University and National Institutes of Health. Phase I Intratumoral Dendritic Cell Immunotherapy in Thermally Ablated Liver Metastases; ClinicalTrials.gov identifier: NCT00185874. www.ClinicalTrials.gov, 2005.

6. Triozzi, P.L., et al., Intratumoral injection of dendritic cells derived in vitro in patients with metastatic cancer. Cancer, 2000. 89(12): p. 2646-54.

7. Tong, Y., W. Song, and R.G. Crystal, Combined intratumoral injection of bone marrow-derived dendritic cells and systemic chemotherapy to treat pre-existing murine tumors. Cancer Research, 2001. 61(20): p. 7530-5.

8. Song, W. and R. Levy, Therapeutic vaccination against murine lymphoma y intratumoral injection of naive dendritic cells. Cancer Research, 2005. 65(13): p. 5958-64.

9. Tanaka, K., et al., Intratumoral injection of immature dendritic cells enhances antitumor effect of hyperthermia using magnetic nanoparticles. International Journal of Cancer, 2005. 116(4): p. 624-33.

10.Teitz-Tennenbaum, S.,et al., Radiotherapy potentiates the therapeutic efficacy of intratumoral dendritic cell administration. Cancer Research, 2003. 63(23): p. 8466-75.

11.Machlenkin, A., et al., Combined dendritic cell cryotherapy of tumor induces sytemic antimetastatic immunity. Clin Cancer Res, 2005. 11(13): p. 4955-61.

12.Ragde, H., W. Cavanagh, and B. Tjoa, Combined intratumoral injection of bone marrow derived dendritic cells and cryotherapy in the treatment of established murine tumors. Unpublished data, 2005.