Pregnancy or breast feeding . 9. Active second invasive malignancy, other than basal cell carcinoma of the skin. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 18 of 47 10. Life expectancy of less than 6 months. 11. Patients with contraindications to known allergies to CYP and/or Imiquimod . 12. Patients who have received organ transplants. 13. Patients with psychological or geographic conditions that prevent adequate follow - up or compliance with the study protocol. 3.3 Withdrawal Criteria 3.3.1 Reasons for Withdrawal of Patients from Study 1. Patients with clinically significant biochemical , histological and/or radiographic evidence of increasing disease burden since entry into the study may be removed from the study. 2. Patients may be withdrawn from the study in the event of dose limiting toxicities . 3. Patients may be withdrawn from study in the event of protocol non- compliance. 4. Patients may voluntarily withdraw from study, if they decide to do so, for any reason. 3.3.2 Follow-up of Withdrawn Patients 1. A subject withdrawn by virtue of progressive disease will continue to be followed as clinically indicated , as determined by the patient’s physician and will continue to receive standard of care follow-up, as medically indicated and at the discretion of the patient’s physician. 2. A subject withdrawn by virtue of limiting treatment- related toxicity will be followed as clinically indicated , as determined by the patient’s physician per standard of care, and/or until resolution of the adverse event(s). 3. All subjects will be requested to adhere to the protocol schedule for clinic visits as far as is reasonable and as clinically indicated . 4. Blood draws and protocol related data will be requested and collected according to the protocol schedule as is reasonable and as clinically indicated . 5. As far as is reasonable, data will continue to be collected at the indicated protocol time-points. 3.4 Patient Replacement 3.4.1 Reasons for Replacement 1. In the event of screening failures post -enrollment (i.e., patients without confirmed KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 19 of 47 progressive and/or relapsed SM diagnosis or failure to meet other screening or inclusion criteria), patients will be replaced. 2. Inability of enrolled subjects to tolerate phlebotomy or leukapheresis. 3. Voluntary withdrawal of subjects prior to initiation of treatment. 4. Failure to complete three (3) DC vaccinations. 3.5 Study Schedule 3.5.1 Summary of Pre -treatment Evaluations 1. Obtain informed consent to enroll patients with refractory SM s/p conventional salvage therapy. 2. Completion of screening procedures per study calendar (including determination of TAPA expression in neoplastic cells and/or blood) and pre-treatment evaluation for clinical trial enrollment. 3. Completion of systemic therapy and confirmation of refractory , progressive, and/or relapsed SM. 4. CBC, differential leukocyte counts, and baseline biochemical and/or radiographic evaluation of disease status no more than per study calendar. 5. Pregnancy evaluation. 6. Completed baseline delayed -type hypersensitivity response (DTH) skin tests with specific T APA(s) seven (7) days +/- 3 days prior to 1st DC vaccination. 7. Negative infectious disease history, for safe handling of blood/leukapheresis products (including a negative history of HIV, and a negative history of active hepatitis A, B, or C). 8. Phlebotomy/le ukapheresis within 2 weeks +/ - 7 days prior to beginning DC vaccination schedule. 9. Manufacturing of DC vaccine bank. 10. Baseline Immune Assays and tissue TAPA levels. 11. Initiation of treatment a 5-day course of CYP, which may be taken at home, beginning 5-7 days prior to each DC vaccination. 3.5.2 Summary of Treatment Visits and Procedures 1. Please refer to Appendix 1, Study Calendar KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 20 of 47 3.6 Safety Endpoints The main endpoints for this Phase I/II trial are safety and immune efficacy. Up to six (6) patients will be enrolled in the Phase I/toxicity stage of the study. Early stopping rules will be in place to protect patients from excessive toxicity. The trial will be halted if Dose Limiting Toxicity (DLT, defined below) occurs in two (2) or more of six (6) patients receiving DC vaccination. If DLTs are observed in no more than 1/6 patients during the Phase I/toxicity stage, the treatment will advance to the Phase II/immune efficacy stage. Immune efficacy will be evaluated in all patients ( see below for stopping rule regarding lack of immune efficacy ). Toxicity will be graded according to NCI-CTCAE, version 4.0. 3.6.1 Rules Based on Dose Limiting Toxicity 3.6.2 Definition of Adverse Event and Adverse Reaction 1. An adverse event is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. More specifically, an adverse event can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, without any judgment about causality. An adverse event can arise from any use of the drug (e.g., off -label use, use in combination with another drug) and from any route of administration, formulation, or dose, including an overdose. 2. An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse reactions are a subset of all suspected adverse reactions for which there is reason to conclude that the drug caused the event. 3.6.3 Causality 1. Suspected A suspected adverse reaction is defined as any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, “reasonable possibility” indicates that there is evidence to suggest a causal relationship between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse reaction. Patients with DLTs Action 0-1/6 Proceed to the immune efficacy stage of the study ≥ 2/6 Stop study KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 21 of 47 2. Unexpected An adverse event or suspected adverse reaction is considered unexpected if it is not listed in the investigator brochure or package insert(s), or is not listed at the specificity or severity that has been observed, or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsew here in the current application. Adverse events that would be anticipated to occur as part of the disease process are considered unexpected for the purposes of reporting because they would not be listed in the investigator brochure. For example, a certain number of non- acute deaths in a cancer trial would be anticipated as an outcome of the underlying disease, but such deaths would generally not be listed as a suspected adverse reaction in the investigator brochure. Some adverse events are listed in the I nvestigator Brochure as occurring with the same class of drugs, or as anticipated from the pharmacological properties of the drug, even though they have not been observed with the drug under investigation. Such events would be considered unexpected until they have been observed with the drug under investigation. For example, although angioedema is anticipated to occur in some patients exposed to drugs in the ACE inhibitor class and angioedema would be described in the investigator brochure as a class effect, the first case of angioedema observed with the drug under investigation should be considered unexpected for reporting purposes. 3. Serious An adverse event or suspected adverse reaction is considered serious if, in the view of either the investigator or sponsor, it results in any of the following outcomes: a. Death b. Life-threatening adverse event c. Inpatient hospitalization or prolongation of exis ting hospitalization d. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life function e. Congenital anomaly/birth defect f. Important medical events that may not result in death, are life -threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such me dical events include allergic bronchospasm requiring intensive treatment in an emergency room KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 22 of 47 or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 4. Life-threatening An adverse event or suspected adverse reaction is considered life-threatening if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. 3.6.4 Recording of Adverse Events (AE) 1. All grade 3 and above AE will be recorded whether or not the event is believed to be associated with use of the study drug. Data about these events and their severity will be recorded using the NCI CTCAE version 4.0. 2. The Investigator will assign attribution of the possible association of the event with use of the investigational drug, and this information will be recorded using the classification system listed below: a. Unrelated to investigational drug/intervention: The AE is clearly NOT related to the intervention b. Unlikely related to investigational drug/intervention: The AE is doubtfully related to the intervention c. Related to investigational drug/intervention: • Possible: The AE may be related to the intervention • Probable: The AE is likely related to the intervention • Definite: The AE is clearly related to the intervention 3. Signs or symptoms reported as AE will be graded and recorded by the Investigator according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI -CTCAE) v. 4.0. When specific AE are not listed in the NCI - CTCAE v. 4.0, they will be graded by the Investigator as none, mild, moderate, or severe according to the following grades and definitions: a. Grade 0: No AE (or within normal limits) b. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated c. Grade 2: Moderate; minimal, local, or noninvasive intervention (e.g., KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 23 of 47 packing, cautery) indicated; limiting age -appropriate instrumental activities of daily living (ADL) d. Grade 3: Severe or medically significant but not immediately life - threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self -care ADL e. Grade 4: Life-threatening consequences; urgent intervention indicated f. Grade 5: Death related to AE 3.6.5 Follow-up of Adverse Events 1. All adverse events will be followed with appropriate medical management until resolved. 2. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event. 3. For selected adverse events for which administration of the investigational drug was stopped, a re -challenge of the subject with the investigational drug may be conducted if considered both safe and ethical by the Investigator. 3.6.6 Adverse Event Monitoring 1. All AE, whether or not unexpected, and whether or not considered to be associated with the use of the study drug, will be recorded, as noted above. 2. The Principal Investigator (PI) will assess all AE and determine reportability requirements to the Food and Drug Administration (FDA), if it meets the FDA reporting criteria. 3. All AE recorded will be reviewed by the study PI on a weekly basis and the Institutional Protocol Review Committee (IPRC) and/or the Institutional Review Board (IRB) on a monthly basis, or as deemed necessary by the study PI. The PI/IPRC will review and discuss at each meeting the selected toxicity, the toxicity grade, and the attribution of the relationship of the AE to study drug/treatment. 3.6.7 Definition of Dose -Limiting Toxicity (DLT) 1. Grade III or higher allergic reaction. Grade III is defined as symptomatic bronchospas m requiring medication, edema or angioedema, and Grade IV is defined as anaphylaxis. 2. Grade II or higher autoimmune reaction. Grade II is defined as an autoimmune reaction involving a non- essential organ or function requiring treatment. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 24 of 47 3. Grade III or higher hematologic or non- hematologic toxicity including fever (> 40o C for > 24 hours). 4. Grade III injection site reaction (severe or prolonged ulceration or necrosis). 5. Toxicity will be graded according to NCI-CTCAE, version 4.0. 3.7 Immune Efficacy Endpoint 3.7.1 Immune Efficacy (IE) Rules The main secondary endpoint of this Phase I/II clinical study is immune efficacy (IE), defined as “detection of a TAPA -specific immune response in SM patients receiving DC vaccination” . Immune responses will be evaluated, as described, in all patients enrolled on the study. Up to six (6) patients will receive the planned six three (3) DC vaccinations before with an interim analysis of IE performed on Day 22 and Day 45 of the sixth patient (69). With regard to IE, the accrual goal will be up to seventeen (17) patients. Stopping criteria, with regard to IE, will be based on defined immune responses and will follow a Simon 2- stage design with a null hypothesis of 5% IE (p 0 = 0.05) and alternative hypothesis of 35% IE (p 1 = 0.35) with desired significance level (α) and desired power (1-β) of 0.05 and 0.9, respectively. Interim analysis of immune response will be conducted after accrual of six (6) subjects completing the planned three (3) DC vaccine doses . If no immune responses are observed at interim analysis (0/6 patients), early stopping will be considered based on lack of efficacy of the intervention. With this rule, the probability of early termin ation (if the alternative hypothesis is true) is seven and one -half percent (7.5%). If three (3) or more patients, out of a total of seventeen (17) develop TAPA - specific immune responses, then the null hypothesis of 5% IE can be rejected, and results will be deemed favorable to move to a formal phase II study. Analysis to determine IE will be performed in all patients after receiving six three (3) DC vaccine doses . Patients who are unable to complete the planned six three (3) DC vaccine doses will be withdrawn from the study. 1. Immune Efficacy Endpoint will be determined as follows: a. Positive T -cell cytokine IFN -ɣ, and/or TNF -α, and/or IL -17 ELISpot assay for ex vivo T cell cytokine expression following stimulation with relevant TAPA. For each patient sample the I FN-γ ELISpot assay (and/or TNF-α or IL-17) will be performed in triplicate using a minimum of three wells per replicate, as described by the manufacturer. b. Positive DTH skin tests with relevant TAPA (DTH skin tests will be performed on subject’s forearm or within 5 cm from the site of prior DC vaccination, if possible). KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 25 of 47 3.8 Reasons for Discontinuation of Study 1. High frequency of limiting toxicities. 2. Lack of immune response. 3. Non-availability of reagents required for DC manufacture (including non - availability of acceptable alternative reagents). 4. Non-availability of Imiquimod and/or oral CYP, in the absence of an available alternative . 3.9 Potential Risks and Benef its 3.9.1 Known Toxicities Associated with DC Vaccination 1. DC vaccination strategies have been studied clinically in many different diseases. This particular vaccine has been tested in very few patients. Both monocyte -derived DCs (as being proposed for this study) and CD34+ -derived DCs have been used in the presence of serum -free or fetal calf serum -containing mediums. Because these cells have been generated from autologous cells, their administration either intravenously (IV), subcutaneously (SC) or intradermally (ID) has not been associated with any significant adverse effects, with the exception of low grade fever and local reactions, such as erythema, at the sites of injection. 2. In a recently conducted p hase I clinical trial of DC vaccination of patients with early -stage cervical cancer (BB -IND 11307), no adverse side effects were observed or reported by subjects following immunization beyond the immediate discomfort associated with injection (10). However, local reactions (mild erythema, swelling/induration, pruritus) were noticed at the subcutaneous vaccination sites that increased with the number of vaccinations in most of the patients. Also, a slight enlargement in the draining lymph node in the groin after DC injections was observed in some of the patients. The patients were monitored during treatment with complete blood counts and serum chemistries that included liver and renal function tests and electrolytes. No alterations in liver and renal function were detected. The safety of DC vaccination was also recently demonstrated in a study combining autologous DC vacc ine against the melanoma antigen MART -1 and the cytotoxic T lymphocyte associated antigen 4 (CT L-4) antagonist tremelimumab (70). The only toxicity reported in this study was related to grade I- II pruritic skin eruptions previously associated with CTLA4 antagonist s. No toxicity attributed to DC vaccination alone was reported. 3. One of the major concerns regarding DC vaccination with self -tumor antigens is the possible induction of autoimmunity. Vitiligo has been seen in some melanoma KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 26 of 47 patients, but no cases of severe autoimmune reactions have been reported. Some TAPAs used in this study have not been explored as targets for immunotherapy in large numbers of patients. Therefore, the clinical data supporting their safety in humans is li mited (30). Nevertheless, the available data indicating these TAPAs are selectively expressed in tumor cells and normal testis (but not in any normal tissues) suggest the immune responses generated by TAPA -pulsed DC therapy will only affect tumor cells. Further evidence supporting the safety of TAPA immuno - targeting is the lack of toxicity associated with spontaneous development of anti - TAPA antibodies following vasectomy (25). Despite these observations, the possible risks of stimulating Th17 responses through DC vaccination in SM patients, are not known. Interestingly, a number of studies have documented contradictory results on the effects of stimulating Th17 T cell responses, with some showing potent anti -tumor activity for Th17 T cells, while others reporting pro- angiogenic and tumor -promoting properties ascribed to Th17 immune responses (71). Moreover, since Th17 responses are pro- inflammatory, they may be associated with as yet u nknown side effects. Despite these potential problems, the available evidence suggests the risk of developing autoimmune complications/disease should be minimal. Also, since the majority of these TAPAs are expressed in spermatids, there is also a remote po ssibility that normal testicular function may be affected. All subjects will be monitored closely for treatment - related adverse events and dose- limiting toxicities. 4.0 METHODS AND ASSE SSMENTS 4.1 Contraception and Pregnancy Testing Either a female or male of reproductive capacity wishing to participate in this study must be using, or agree to use, one or more types of birth control during the entire study and for 3 months after completing the study. These may include condoms, diaphragms, birth control pills, spermicidal gels or foams, anti -gonadotropin injections, intrauterine devices (IUD), surgical sterilization, or subcutaneous implants. Another choice is for a subject’s sexual partner to use one of these birth control methods. W omen of reproductive capacity will be requested to undergo a urine pregnancy test before completion of the post -screening informed consent process. 4.2 Screening, Study Visits and Procedures 4.2.1 Screening Visits and Procedures 1. Subjects must be adult patients with confirmed progressive and/or refractory SM and no available, potentially curative therapeutic option. Informed consent will be sought for completion of screening procedures. 2. Screening evaluation will include the following: KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 27 of 47 a. History and physica l examination. b. Karnofsky performance status. c. Evaluation of concomitant medications. d. CBC and differential leukocyte count. e. Tests for hepatic function and renal function. f. Pregnancy evaluation and birth control agreement. g. Negative infectious disease history, for safe handling of blood/leukapheresis products (including a negative history of HIV, and a negative history of active hepatitis A, B, or C). h. Diagnostic studies, including biopsies (if indicated), appropriate imaging studies, serum and/or urine tumor ma rker measurements (if indicated), will be obtained within three (3) weeks ±14 days prior to vaccination. i. Confirmation of expression of one (1) or more TAPA, by either RT -PCR, immunohistochemistry, Western blotting, or ELISA, in neoplastic cells prior to enrollment . For HER -2/Neu expression a positive FISH will be considered adequate. 4.2.2 Study Visits and Procedures 1. Peripheral blood mononuclear cells will be harvested by phlebotomy and/or leukapheresis, via peripheral or central venous access . Patients must be willing to provide at least 250 mL, and up to 500 mL, of whole blood obtained by phlebotomy and/or consent to leukapheresis for DC generation. If leukapheresis is required, this procedure will require a median duration of 2-3 hours on a leukapheresis machine and a median volume of processed whole blood of 150 ml/kg body weight. This can be done with a large bore peripheral IV but in select patients it may require a temporary central line during the procedure. The end result is a rich col lection of nucleated white blood cells from which to extract DC precursors. The total volume of removed blood product is a small bag containing approximately 100 cc of plasma which contains the desired cells. Central venous access will be placed and used f or phlebotomy/leukapheresis only if blood cannot be obtained by peripheral access. Placement of central venous access will be done at the hospital as an outpatient and with a separate surgical consent. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 28 of 47 Phlebotomy/leukapheresis will be conducted within two (2) weeks +/ - 7 days of the first DC vaccination. 2. The patient will receive a 5-day course of CYP ( 1.6 mg/Kg/day, with a maximum of 100 mg/day), which may be taken at home, beginning 5- 7 days prior to each DC vaccination . 3. TAPA- pulsed DC will be administe red at a vaccine dose of up to 1 x 107 DC, in injection -grade saline solution to bring total volume to 1 mL, if necessary. The vaccine total volume will be up to 1.0 mL and will be administered in 4 separate intradermal (ID) injections (0.25ml per injectio n) in the upper anterior thigh (inguinal node region) or the upper outer arm (axillary node region) in order to increase proximity to local lymph node draining basins and optimize propagation of TAPA -pulsed DCs to secondary lymphoid organs ( 72). If clinically feasible, DC vaccination will be alternated between the right and left sides of either the upper anterior thigh, or the upper oute r arm. If there is the history of a prior inguinal lymphadenectomy, lower extremity lymphedema, prior inguinal hernia repair, or, the history of an axillary lymph node dissection, or upper extremity lymphedema, then the non- affected site/anatomic region would be preferred . The three (3) DC vaccines will be administered at 7-day intervals to maximize patient convenience and protocol adherence. Patients will be observed for up to one (1) to three (3) hours following each vaccine dose administration. 4. Vaccination Schedule: Day 1 Day 8 Day 15 Vaccine 1 Vaccine 2 Vaccine 3 Imiquimod cream will be administered at a dose of ~10 mg after each intradermal injection. Immediately after the injections, the area will be cleaned by gently tapping with an alcohol swab (such as BD Alcohol Swabs). When the area is dry, Imiquimod (Ald ara cream) will be applied over the injection sites, at the dose of about 4 mm of cream, corresponding to 10 mg Imiquimod. The area will be covered with a Band -Aid type patch and the patient will be instructed not to wash it or wipe it until the following day, when the patient will remove the medication by washing the area with mild soap and water. If itchiness is present, the patient will be instructed to apply topical anti -histamine cream as appropriate. Steroid -based medication at the site of the injection are to be avoided. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 29 of 47 5. Blood for immune assays and TAPA levels (up to 100 mL) will be drawn 1 to 7 days +/- 3 days before the 1st DC vaccination, and on days twenty -two (22) and day forty -five (45) +/ - 3 days after the third vaccination. 6. DTH skin tests to assess cellular immune responses against relevant TAPAs will be conducted at the same time of blood immune assays (see above). DTH response will be determined and the response measured, between 2 and 3 days following the skin test, the results of which can be read by the study coordinator or by an appropriate study coordinator designated health care professional. 7. Evaluation of tumor responses: Immune responses shall be evaluated 7 days (Day 22) and 30 days (Day 45) following the last ( 3rd) DC vaccination, with imaging as clinically indicated (See Appendix 3). Patients may undergo evaluation of disease status anytime, at the discretion of PI, if disease progression is suspected. 8. Patient Enrollment Once the Phase I stage of the study is completed (subject 6 receives the 3rd vaccination dose and is evaluated for toxicity ) the Phase II stage of the study will begin with enrollment of subject # 7. 9.