**6. Points to consider: Safety, regulatory and ethical issues**

Immunostimulatory trials in various cancer entities has often been judged as limited in the impact but have always been seen as at least non toxic and so not harming the patients. AEs seen in vaccine trials have in most cases be limited to local injection side reactions. Vaccines which use a cytokine in addition reported flu-like symptoms but not above grade 2. If

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CTLA4-antibodies are used or Tregs-cells depleted some aspects of autoimmunity and other immunological break through events has been seen up to grade 3. In a combination of chemotherapy with vaccine (see GVAX) there were more deaths and diminished OS noticed in the combination arm.

AEs seen in the sipuleucel-T trials could be explained by the i.v. re-infusion of cells which had been manipulated outside the body as the AEs were as common in the verum group (stimulated T-cell re-infusion) as in the control group (unstimulated T-cell re-infusion). Also in other clinical trials severe up to fatal acute infusion reactions had caused concerns after re-infusion of immune cells. While for sipuleucel-T the total amount of cells is unknown only the total amount of CD54+ cells is adjusted to a minimum of 5 × 108 APCs - patients with fatal AE received 2 × 109 and 10 × 1010 gene modified T-cells respectively (Brentjens et al., 2010; Morgan et al., 2010). So one could state that for vaccines based on DCs the i.v. application route seems not to be ideal and even more doubtful as other routes of application with a better safety profile are well established (e. g. intranodal (inguinal lyph node) (Mu et al., 2005), subcutaneous (Vonderheide et al., 2004; Hildenbrand et al., 2007) or intradermal re-infusion of DCs (Mu et al., 2005; Su et al., 2005; Waeckerle-Men et al., 2006; Hildenbrand et al., 2007; Sampson et al., 2009; Toh et al., 2009)) in urological and other tumor entities.

Cancer vaccines are a diverse array of therapeutics with several mechanisms of action – and some times the mode of action is not well known even for products having succeeded in late-stage trials. So cancer vaccines are a challenge for the regulators, researchers and sponsors in several aspects: i) preclinical testing and the need for relevant animal models, ii) finding the proper dose, iii) trial design especially assessment of the right end point, and iv) attempts to conduct cancer vaccine trials in early state patients.

Besides some basic ethical questions – e.g. is it ethical to do a placebo treatment in a cancer patient at all – an other challenge in cancer vaccine research is to investigate what healthcare strategies and interventions offer the greatest benefits to individual patients and the population as a whole, that means to do comparative effectiveness research (CER) which to date has not been performed in the cancer vaccine field at all (Stewart et al., 2010). Undertaking any type of CER in oncology, calls for an outcomes measurement that can capture quality-of-life (QOL) measures. Most treatment decisions in cancer care are made with palliative intent or with probabilities of cure that must be weighed against the toxicity side-effects of the treatment. Although great strides have been made in the use of targeted therapies with more favourable side-effect profiles, oncologists remain extremely aware of the clinical tradeoffs between length of life and quality of life. Last points to mention are attempts to use earlier patients or even to test cancer vaccines in the preventive setting (Gray et al., 2008) and to define special vaccine adjuvants tailored to be used in the new therapeutic area of therapeutic cancer vaccines (Dubensky & Reed, 2010; Young, 2010).

#### **7. References**


CTLA4-antibodies are used or Tregs-cells depleted some aspects of autoimmunity and other immunological break through events has been seen up to grade 3. In a combination of chemotherapy with vaccine (see GVAX) there were more deaths and diminished OS noticed

AEs seen in the sipuleucel-T trials could be explained by the i.v. re-infusion of cells which had been manipulated outside the body as the AEs were as common in the verum group (stimulated T-cell re-infusion) as in the control group (unstimulated T-cell re-infusion). Also in other clinical trials severe up to fatal acute infusion reactions had caused concerns after re-infusion of immune cells. While for sipuleucel-T the total amount of cells is unknown only the total amount of CD54+ cells is adjusted to a minimum of 5 × 108 APCs - patients with fatal AE received 2 × 109 and 10 × 1010 gene modified T-cells respectively (Brentjens et al., 2010; Morgan et al., 2010). So one could state that for vaccines based on DCs the i.v. application route seems not to be ideal and even more doubtful as other routes of application with a better safety profile are well established (e. g. intranodal (inguinal lyph node) (Mu et al., 2005), subcutaneous (Vonderheide et al., 2004; Hildenbrand et al., 2007) or intradermal re-infusion of DCs (Mu et al., 2005; Su et al., 2005; Waeckerle-Men et al., 2006; Hildenbrand et al., 2007; Sampson et al., 2009; Toh et al., 2009)) in urological and other

Cancer vaccines are a diverse array of therapeutics with several mechanisms of action – and some times the mode of action is not well known even for products having succeeded in late-stage trials. So cancer vaccines are a challenge for the regulators, researchers and sponsors in several aspects: i) preclinical testing and the need for relevant animal models, ii) finding the proper dose, iii) trial design especially assessment of the right end point, and iv)

Besides some basic ethical questions – e.g. is it ethical to do a placebo treatment in a cancer patient at all – an other challenge in cancer vaccine research is to investigate what healthcare strategies and interventions offer the greatest benefits to individual patients and the population as a whole, that means to do comparative effectiveness research (CER) which to date has not been performed in the cancer vaccine field at all (Stewart et al., 2010). Undertaking any type of CER in oncology, calls for an outcomes measurement that can capture quality-of-life (QOL) measures. Most treatment decisions in cancer care are made with palliative intent or with probabilities of cure that must be weighed against the toxicity side-effects of the treatment. Although great strides have been made in the use of targeted therapies with more favourable side-effect profiles, oncologists remain extremely aware of the clinical tradeoffs between length of life and quality of life. Last points to mention are attempts to use earlier patients or even to test cancer vaccines in the preventive setting (Gray et al., 2008) and to define special vaccine adjuvants tailored to be used in the new therapeutic area of therapeutic cancer vaccines (Dubensky & Reed, 2010; Young, 2010).

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immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic,


**15** 

**Skeletal Related Events in Prostate Cancer:** 

In western countries, prostate cancer is the most common non-dermatological malignant disease in men. An estimated 217730 new cases will have been diagnosed in 2010 in the USA (Jemal A et al., 2010) and 382250 cases were diagnosed in 2008 in Europe (Ferlay J et al., 2010),

Bone is one of the most common sites of metastatic disease in patients with cancer, affecting approximately 400,000 patients each year. Nearly 70% of patients with advanced breast or prostate cancer will experience bone lesions; 50% of these patients will develop a secondary skeletal complications which represents a substantial disease and economic burden

The pathologic penetration of bone by tumour tissue can lead to numerous skeletal-related events, such as hypercalcemia, fracture, spinal cord compression, and potentially debilitating bone pain (Berruti A et al., 2002). Often these consequences result in the need for radiological and surgical intervention. Along with these therapies, pharmacological management is required to help reduce symptoms, prevent recurrence and further improve

Prostate carcinoma is the most common visceral malignancy and the second leading cause of death from cancer in men (Diamond T et al., 2004). Androgen-deprivation therapy (ADT), either alone (as depot gonadotrophin releasing hormone agonist) or in combination with antiandrogens (such as flutamide, bicalutamide, or cyproterone acetate), is recommended treatment for men with metastatic or locally advanced, non-metastatic prostate carcinoma (Fowler JE et al., 2002). Although it has been demonstrated that this form of therapy significantly reduces tumour growth and improves survival beyond 3 years after completion (Bolla M et al., 1997), there is growing concern regarding the negative effects of ADT on the skeleton. Accelerated bone loss, osteoporosis, and a potential for increased. Fracture rates have been reported in men with prostate carcinoma who are receiving ADT. Because many patients who present with prostate carcinoma are elderly and may have

accounting for 28% and 22% of new non-cutaneous cancer diagnoses, respectively.

**1. Introduction** 

(Schulman KL & Kohles J, 2007).

patients' quality of life.

**Important Therapeutic Considerations** 

Miguel Álvarez Múgica1, Jesús Mª Fernández Gómez2,3, Antonio Jalón Monzón2, Verónica Bulnes Vázquez4, Erasmo Miguelez1 and Francisco Valle González1

*1Urology Department, Hospital Valle del Nalón* 

*4Radiology Department, Hospital Álvarez Buylla* 

*2Urology Department. HUCA* 

*3University of Oviedo* 

*Spain* 

