Tumor-Pulsed Dendritic Cells Used as a Tumor Vaccine
Tumor-Pulsed Dendritic Cells Used as a Tumor Vaccine
This study is being conducted to determine the efficacy, side effects, and toxicity of an
 investigational vaccine that consists of tumor-pulsed dendritic cells administered with an
 immune stimulating drug called interleukin-2 (IL-2). Dendritic cells are immune cells that
 are obtained from a subject's blood and are important in the body's immune response to
 foreign substances. This study will examine the response of a subject's immune system after
 receiving several vaccinations containing their own dendritic cells which have been exposed
 to dead fragments of their cancer cells in the laboratory. This may result in sensitizing a
 subject's dendritic cells to their cancer cells so that their dendritic cells will react with
 other cells of the immune system and attack the cancer. It has been shown in the laboratory
 that dendritic cells exposed to cancer cell fragments can provide lymphocytes (a type of
 white blood cell) with signals they require in order to become fully activated and acquire
 the ability to kill cancer cells.
Pretreatment screening: If a subject decides to participate in this study they will first be
 presented the informed consent document to read and review with the Principal Investigator
 (or his designee) to go over each aspect of the study and answer any questions. Once the
 patient has consented, they will first be screened to make sure they meet the eligibility
 criteria. The screening process is done to make sure that it is appropriate for the subject
 to participate in this study. This process will include a review of their medical history, a
 complete physical examination, standard blood tests, an EKG (an electrocardiogram), a chest
 x-ray and if it is possible for them to become pregnant, a pregnancy test. These tests are
 normally performed on patients prior to receiving chemotherapy for cancer. In addition to
 these tests which are normally performed, blood will be obtained for tests which are specific
 for this investigational study.

 These study specific tests include a blood test to determine whether a subject may be
 infected with the hepatitis B virus or the AIDS virus, and blood tests to determine the
 ability of their immune system to respond to normal stimulation. A doctor will also order CT
 scans or nuclear medicine scans to measure the extent of the subject's cancer because the
 study therapy has a possibility of shrinking the tumor and this will be determined by
 measuring each subject's disease before and after therapy.

 At the time of this initial evaluation subjects will have skin tests that will determine
 their ability to mount an immune response to infectious agents (such as tetanus, measles,
 mumps) that they have been exposed to or vaccinated against. If a subject fails to
 demonstrate a response to all the skin tests, they will not be allowed to participate in this
 study because such lack of response indicates that their immune system may not respond to the
 therapy planned in this study.

 Vaccine therapy: In order to make a vaccine from a subject's tumor they must have surgical
 removal of some tumor in order to provide tumor cells. The doctor will determine if a subject
 has colorectal cancer cells that are easily obtainable. However, if a subject already has an
 available frozen tumor specimen at the University of Michigan, that may be used for the
 vaccine preparation instead of undergoing another surgical procedure. This surgery may be
 done solely for the purpose of participating in this research and may not otherwise benefit a
 subject. A separate consent form will be required for any surgery a subject undergoes.

 The cancer cells obtained from each subject will be taken to the laboratory where they will
 be separated into single cells, disrupted to make cell fragments, radiated to kill the cells
 and then mixed with your dendritic cells. The dendritic cells will be obtained from the
 peripheral blood. Subjects will undergo a procedure called leukapheresis that involves
 placing a large needle (central line) in a vein in each of their arms. These central lines
 will be inserted under local anesthesia (subjects will remain awake…only the site of the
 insertion will be "frozen"). Blood exits from one needle and is processed through a machine
 that selectively removes one kind of white blood cell and then returns the other elements of
 the blood back to their body. The leukapheresis procedure generally lasts three to four
 hours. Following the procedure, the dendritic cells will be cultured in the laboratory to
 increase the number of dendritic cells. This procedure takes about 2 days.

 The tumor-exposed dendritic cell vaccine will be administered as an intradermal (into the
 skin) injection into a subject's thigh or arm on days 1, 15 and 29 of study treatment.
 Additionally, they will receive IL-2 by subcutaneous injection daily for 4 days after each
 vaccination.

 Four weeks after their last vaccination, subjects will undergo skin testing to determine if
 they are reactive to their tumor cells. White blood cells will also be obtained by a second
 leukapheresis procedure to determine, via research tests in the laboratory, if their
 circulating immune cells have developed the capacity to respond to their cancer cells. This
 skin testing and leukapheresis are for research purposes.

 Also, 4 weeks after subjects receive their last vaccination, they will have x-rays and/or CT
 scans done to determine whether their disease has responded to the immune therapy. If their
 cancer has not worsened or if it has shrunk, then they will be offered the option to receive
 additional vaccinations using the tumor-pulsed dendritic cells providing that they did not
 experience severe toxicity with the first series of vaccinations and provided there is enough
 vaccine material available. The additional vaccinations would be done using the same
 procedure and schedule as the previous vaccinations until there is evidence that the
 subject's disease has started to grow or worsen. This includes leukapheresis, vaccination,
 and IL-2 administration. Re-treatments will be offered until a subject's disease gets worse
 or tumor cells are no longer available to produce vaccines. A subject's study participation
 will end with the leukopheresis and tumor evaluation 4 weeks following their last series of
 vaccinations.

 Blood Drawing: The maximum amount of blood, for standard tests and research purposes that
 will be drawn during the 10 weeks will be a total of 100ccs, which is approximately 20
 teaspoons, which is equivalent to approximately 7 tablespoons over the 12 week time period.

 The length of time a subject would be on this study is a minimum of nine weeks. If the
 physician determines that a subject is benefiting from this study, they may continue repeat
 vaccinations for as long as they continue to have clinical benefit from the study and vaccine
 is available. During the study, if other therapy alternatives become clinically indicated,
 they will be discussed with the subject. Also, if there are any significant new findings
 developed over the course of this research which may affect a subject's willingness to
 participate, they will be told of them.
Inclusion Criteria:

 1. Patients must have metastatic colorectal cancer. Patients are eligible whether they
 are previously untreated or had received prior treatment.

 2. Patients must have a source of autologous tumor that can be easily harvested. This
 includes patients with subcutaneous or cutaneous metastases, patients with easily
 excisable lymph nodes containing metastatic tumor, and patients with malignant pleural
 effusions or ascites. In addition, some patients who undergo a planned curative
 operation are found at that time of surgery to be unresectable and these patients
 could have a sample of tumor resected at that time to be eligible for this study.

 3. Karnofsky performance status equal to or greater than 70%.

 4. Life expectancy of at least three months.

 5. Patients must have evaluable or measurable disease in addition to the disease that
 will be surgically removed for the purposes of formulating the autologous vaccine.

 6. Adequate baseline hematopoietic function:

 1. platelet count equal to or greater than 100,000/mm3

 2. total white blood count equal to or greater than 3,000/mm3

 7. Patients must not have received any antineoplastic chemotherapy or immunotherapy for
 the four weeks preceding entry onto the study (six weeks for nitrosoureas and
 mitomycin-C).

 8. Patients must not have received irradiation for the four weeks prior to entry onto the
 study.

 9. Ability to give informed consent.

 Exclusion Criteria

 1. Patients may not have received prior antitumor vaccines.

 2. History of any autoimmune diseases (e.g. SLE, rheumatoid arthritis, myasthenia
 gravis).

 3. Active infection (bacterial, fungal, or viral), or active bleeding (e.g. hemoptysis,
 GI bleeding).

 4. Pregnancy or lactation; women of childbearing potential and men must use effective
 contraception during the course of this clinical trial.

 5. Uncontrolled angina, arrhythmias, bronchospasm, hypertension, hyperglycemia or
 hypercalcemia.

 6. History of corticosteroid use in the four weeks preceding entry onto the clinical
 study.

 7. Patients who require corticosteroids.

 8. Evidence of HIV infection or AIDS and/or testing positive for HBSAg.

 9. Any medical or psychiatric illness which in the opinion of the clinical investigators
 would compromise the patients ability to tolerate this treatment.

 10. Patients who require anticoagulation.

 11. There is no exclusion for sex or ethnic background.