The potential benefits may include reduction and/or remission of the subject’s brain cancer. Because this procedure is experimental, it cannot be guaranteed that subjects will receive any benefit as a result of participating in this research study. The information collected in this research may help scientists better understand the mechanisms involved in the immune system’s ability to fight cancer. If such an understanding comes from this research, then it may benefit society b y furthering the development of improved treatment methods for human malignant brain tumors in the future. Re-MATC H Protocol Page 93 of 106 Version: 20180628 24.2 Potential Risks 24.2.1 ALLERGIC REACTIONS TO DC IMMUNIZATION OR TTRNA- XALT Injection of antigen presenting cells may result in an allergic reaction, which c ould include redness and swelling at the injection site, itching, hives, low blood pressure, difficulty breathing, or in the most extreme circumstances, death. In addition, if the immune system becomes overly activated, potential discomforts may include pain, redness and swelling at the injection site. The risks associated with the injection of autologous lymphocytes for immunotherapy in humans are currently unknown. The best current assessment of potential risks of TTRNA -xALT can be gathered from the ex tensive experience gained at our institution and others in autologous PBSCT using mobilized progenitors . We have experienced no grade III or IV toxicities associated with infusion of autologous lymphocytes in patients who have received mobilized PBSCT. A recent review describing management of toxicities associated with this procedure describes only complications associated with the consolidation and conditioning regimens utilized in stem cell transplantation, as well as the post -transplant period where p atients exhibit profound neutropenia. Patients may experience an allergic reaction to preserved cells or other transfusion associated side effects such as pain at the injection site, mild swelling or edema, hypotension, or shortness of breath. 24.2.2 C EREBRAL EDEMA Cerebral edema may be secondary to the disease process itself, the surgical procedure, necrosis from previous radiation, or inflammation due to immune infiltration of the brain or destruction of tumor cells. Symptoms may include, but are not limited to , severe headache, confusion, lethargy, unresponsiveness, coma, or focal neurological deficits. Patients will be monitored throughout the course of the study and those patients with any signs or symptoms of cerebral edema may need their steroid doses incr eased, treatment with an osmotic diuretic, or surgical decompression. Edema that fails to respond to aggressive therapy may lead to permanent neurological impairment. The probability of this risk can be predicted to some degree based upon tumor size, location, pre -operative neurological impairment, and post -operative course prior to DC injections. Patients will be monitored throughout the course of the study. 24.2.3 I NFECTION The DC injections or the TTRNA -xALT may include the risk of infection due to potential contamination of the DCs or leukocyte product in the laboratory. This may result in localized redness, swelling, or induration at the injection site. In the most extreme situation, this may lead to systemic bacterial/fungal sepsis and possibly death. T he probability of this risk is relatively low, given the small injection volume (1 mL divided between >2 intradermal locations) and the fact that the DCs will be strictly tested for sterility prior to each injection. The risk of infection due to potential contamination of the DCs in the laboratory will be minimized by biosafety quality assurance and testing. All cell cultures will be handled under sterile conditions in a core tissue culture facility dedicated to the processing of human cells. Prior to injection into patients, DCs must pass sterility tests in thiglycolate broth, tryptic soy blood agar, and inhibitory Sabouraud agar. Following injections, patients will be monitored throughout the course of the study for any signs and symptoms of infection. There have been no infections to date in the recent VICTORI (IRB #3108- 05-9R4) or ACTIVATE (IRB #5421 -05-1R1) clinical trials testing similar approaches in a similar patient population. If an active infection is suspected, patients will be cultured and t reated with appropriate antibiotics. 24.2.4 D ELAYED AUTOIMMUNE DISEASES It is possible that delayed autoimmune disease(s) may develop as a result of injection with DCs or TTRNA - xALT. This means that the immune system may be stimulated to attack natural tissue in the body. Animal studies have reported the development of autoimmunity in the context of vaccination and recovery from lymphopenia. However, our current experience with DC vaccination in glioma patients has not demonstrated evidence of autoimmunity in treated patients. It therefore, is unknown what the risk of delayed autoimmune disease is for this study. Re-MATC H Protocol Page 94 of 106 Version: 20180628 24.2.5 PHLEBOTOMY Drawing blood or inserting an intravenous catheter into an arm vein may result in bruising or swelling in the area of the insertion, blee ding at the site of the needle puncture, light headedness, fainting and very rarely, local infection, which may be severe. These risks are reduced by the fact that the blood will be drawn by a qualified physician, nurse or phlebotomist (a professional trai ned to draw blood). 24.2.6 L EUKAPHERESIS As with any donation of blood, a variety of minor reactions may occur with leukapheresis , which include fainting, dizziness, or nausea. Uncommon but serious complications may also result, which include bleeding, infection , an adverse reaction to the anticoagulant or replacement fluids, hypocalcemia, hypotension, shock, convulsions, air emboli, heart failure, or the inability to transfuse blood back into the patient. These risks are reduced by the fact that the procedure w ill be performed by qualified staff at a specialized clinical hemapheresis unit. Patients will be carefully monitored throughout the procedure by trained nursing and medical staff. Ca lcium gluconate (2 mg PO) will be given to minimize the risks of hypoca lcemia, fluid supplementation will be given to minimize hypotension, and blood will be routinely screened for HIV , hepatitis, and syphilis to minimize the risk of transmitting infection. 24.2.7 MRI The risks and/or discomforts associated with the performance of MRI include the anxiety produced from being in a tight, enclosed space (claustrophobia). In addition, the machine operates using a large and powerful magnet. The magnetism of the machine attracts certain metals: therefore, people with these metals in their bodies (specifically pacemakers, infusion pumps, metal aneurysm clips, metal prostheses, joints, rods or plates) will be excluded from the study. Patients will also be checked to make sure that they do not bring any metal objects into the MRI facility. Dental fillings are less affected by the magnetic fields generated and are therefore permitted. It will be asked that patients let the physicians conducting this study know of any metal in their bodies other than dental fillings. 24.3 Allergic Reactions to Contrast Agents During the MRI, patients will be given a contrast agent. The agent is given routinely to obtain enhanced MRI scans of the brain. The agent is administered through the vein and requires the placement of an IV catheter. The catheter placement is similar to drawing blood except that the catheter remains in the vein during the time the agent is actively delivered. The risks of a blood draw and insertion of a catheter are similar . There have been a few, rare cases of allergies to the agent used in MRI contrast enhanced scans. Patients with any known severe allergies to contrast agents will be excluded from the study. Patients with mild allergies (i.e., rash only) will be pretrea ted with Tylenol and Benadryl prior to injection of the contrast agent. Re-MATC H Protocol Page 95 of 106 Version: 20180628 24.4 GM-CSF and G -CSF Risks Risks and side effects related to the Filgrastim ( G-CSF) include those which are : Likely (“Likely” refers to a side effect that is expected to occur in more than 20% of patients.) Less Likely (“Less likely” refers to a side effect that is expected to occur in 20% or fewer patients.) Rare, but Serious (These possible risks have been reported in rare occurrences, typically less than 2% of patients. They may be serious if they occur.) • Local irritation (skin) at injection site • Ache or pain inside the bones, increased levels of liver enzymes and uric acid in the blood, low number of platelets in the blood • Allergic reaction, low fever • Enlargement or rupture of the spleen • Worsening of pre -existing skin rashes • Temporary hair loss • Inflammation of a blood vessel in the skin Risks and side effects related to Sargramostim (GM -CSF) include those which are: Likely: Less Likely: Rare, but Serious: • Headache • Bone pain • Muscle and joint pains • Fever and Chills • Rash and itchiness • A feeling of discomfort or not feeling well and/or tiredness • Stomach or abdominal pain or cramps • Weakness • Loss of appetite • Nausea and/or vomiting • Diarrhea • Excessive sweating • Inflammation of a vein through which the drug was given • Redness and pain at the injection site • Weight gain • Fewer platelets in the blood. A low number of platelets causes you to bruise and bleed more easily • Increase in the blood of certain enzymes or bilirubin (a substance that comes from the liver breaking down waste products) which could indicate liver irritation or damage • Elevation in the blood of creatinine which normally is removed from the blood by the kidney and could indicate kidney damage • Fluid build- up in the tissues usually of the lower legs • Severe allergic reaction which can be life threatening with shortness of breath, low blood pressure, and a rapid heart beat • A severe reaction which can cause shortness of breath, a low blood pressure, a rapid heart rate, fever, a feeling of warmth and bac k pain which may occur only with the first dose and not with further doses • An abnormally rapid heat beat • Leakage of fluid into the lungs which may result in shortness of breath and difficulty breathing and/or leakage of fluid into body tissues with puffi ness of legs, arms or abdomen, weight gain and a drop in blood pressure • Inflammation of the lungs which may lead to pain and shortness of breath • A build- up of fluid around the heart which may be painful Re-MATC H Protocol Page 96 of 106 Version: 20180628 24.5 Unknown Risks The overall risk classification of this research is unknown.