.................................... 44 KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 7 of 47 ABSTRACT Patients diagnosed with progressive and/or refractory solid malignancies (SM), who have failed conventional therapy, and have no available, potentially curative therapeutic options, will be candidates for this Phase I/II study. Following confirmation of disease progression and/or refractoriness, eligible patients who agree to participate and sign a consent form will have their tumor cells/tissues and/or blood analyzed for the expression of a specific panel of Tumor Associated Peptide Antigens (TAPAs), including Sp17, ropporin, AKAP -4, PTTG1, Span- xb, Her -2/neu, HM1.24, NY -ESO -1 and MAGE -1. Patients whose tumors express one (1) or more of these TAPAs will undergo phlebotomy and/or leukapheresis performed for generation of autologous DCs. Patient’s DCs will be generated in Kiromic’s Cell Processing GMP facility, according to established Standard Operating Procedures, and activated by pulsing/loading them with the TAPA(s) relevant for each particular patient. Patients will receive five (5) days of low -dose c yclophosphamide prior to each vaccination with TAPA- pulsed DCs to decrease Treg activity. TAPA -pulsed DCs will be administered at a fixed dose of up to 1 X 10 7 DCs following cyclophosphamide administration. DC vaccination schedule will be once every seven (7) days via intradermal (ID) injections for a total of 3 vaccinations. Topical Imiquimod will also be administered once after the TAPA- pulsed DC vaccination, to optimize immune responses. Patients will be followed on a weekly basis (or more frequently if required) to evaluate treatment -related toxicity. Immune efficacy and anti -tumor responses will be evaluated per protocol specifications. Continuation and s topping rules for the study will be defined based on toxicity/tolerability (Phase I) and immune efficacy (Phase II). KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 8 of 47 1.0 BACKGROUND AND S IGNIFICANCE Despite advances in understanding the biology of solid malignancies (SM), and the availability of new treatment options, the vast majority of patients with SM remain incurable (1). This is especially true for elderly patients and those whose disease proves refractory and/or relapses following standard therapy. Therefore, therapeutic options for this patient population are quite limited and novel strategies are desperately needed f or patients with progressive and/or refractory SM. Immunotherapy has recently emerged as a promising treatment strategy for patients with SM (2). Dendritic cells (DCs) are the most potent an tigen -presenting cells (APCs) and are necessary for the efficient priming and activation of naïve T -cells against specific antigens. DCs undergo maturation and activation in the presence of specific immunogenic antigens and serve as a critical link between innate and adaptive immunity resulting in antitumor responses ( 3). It is now possible to generate human DCs in-vitro from monocytes exposed to GM -CSF and IL -4, and DC -based treatments have become one of the most attractive immunotherapeutic strategies for cancer in the last decade. Indeed, DC vaccination studies have been conducted in several different neoplasms ( 4, 5) with variable results. Since most patients with progressive SM display a defective immune response to tumor antigens, the ex-vivo activation of DCs, through their exposure to tumor associated antigens, is an attractive and active area of investigation (6, 7). A variety of early clinical studies have demonstrated the feasibility and promise of using antigen-pulsed DC therapy in patients with SM malignancies including metastatic prostate, hepatocellular, colorectal, renal, cer vical, and breast carcinomas, as well as melanomas and glioblastomas (8-13). The fundamental strategies tested have included pulsing DCs with whole tumor cell lysates or specific tumor -associated antigens (8-13) . Although safe, DC vaccination strategies have resulted in unsatisfactory clinical outcomes attributed to either the poor immunogenicity of the target antigens, suboptimal DC -dosi ng, generation of tolerogenic DC subtypes and activity of suppressor regulatory T -cells (Treg). Thus, results of these preliminary clinical studies indicate the need to optimize DC -based immunotherapy to improve responses in patients with SM. DCs can be s afely generated from blood- derived monocytes in the presence of GM -CSF and IL -4 and administered safely to cancer patients (14, 15) . Moreover, DCs pulsed with specific Tumor Associated Peptide Antigens (TAPAs) are capable of eliciting immune and antitumor responses, without prohibitive toxicity (8-13, 16, 17 ). Despite these advances many questi ons remain on how to improve this immunotherapeutic strategy, including how to best activate DCs with various antigens and cytokine combinations, the characterization of “ideal” TAPAs capable of eliciting strong and durable immune responses in patients with SM, the best vaccine immune adjuvants, the optimal dosing and schedule of DC treatments, how to inhibit inhibitory signals from Tregs and what specific group of patients with SM are best suited for this particular DC -based vaccination approach. To solve these problems several potential strategies have been proposed including the use of more potent and immunogenic TAPAs and/or Th1 polarizing cytokines (18, 19) , enhancement ex-vivo KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 9 of 47 DC maturation and activation through Toll -like receptor (TLR) signaling (20), cross presentation of neoplastic cell -associated antigens (21), stimulation of natural killer cell and/or T -helper activity to generate Th1 polarization in DCs (22), inhibition of immunosuppressive Treg cell populations (23) and regulation of DC migration to regional lymph nodes ( 24), among others. We and others have explored several potential TAPAs as immunotherapeutic targets in different malignancies. These highly immunogenic proteins include Sp17, Ropporin, AKAP -4, PTTG1, Span- xb, Her -2/neu, HM1.24, NY -ESO -1, MAGE -1, and are thought to be potential targets for DC -based immunotherapy based on the following observations: Sperm protein 17 (Sp17) Sp17 is a highly immunogenic spermatozoan protein which has been considered a potential therapeutic target for immunocontraception in the last few years (25). We have identified Sp17 as a novel Cancer -Testis Antigen (CTA) in hematologic and SM. Using RT -PCR, Sp17 transcripts were detected in more than 70% of tumor -cell enriched bone marrow from multiple myeloma (MM) patients. Sp17 gene expression was associated with Sp17 protein translation as demonstrated by Western blot analysis. Importantly, Northern blot analysis and RT -PCR, demonstrated Sp17 expression in normal testis and tumor cells, but not in normal tissues, suggesting Sp17 could serve as an excellent immunotherapeutic target in MM (26). We have cloned the full -length coding sequence of the Sp17 cDNA and successfully generated Sp17 -specific HLA -class I restricted cytotoxic T lymphocyte (CTL) after “pulsing” monocyte -derived DCs with the E. coli -derived recombinant Sp17 protein (14). These Sp17- specific CTLs were abl e to lyse autologous target cells pulsed with recombinant Sp17 protein as well as Sp17- expressing fresh MM cells. Moreover, we have generated a synthetic Sp17 peptide (103- 111) (ILDSSEEDK) capable of inducing HLA - A1 restricted CTL recognition and activati on (27). We have also expanded our evaluation of Sp17 potential as an immunotherapeutic target by recently demonstrating its strong immunogenicity in an ovarian cancer animal model (28) and have recently found Sp17 is expressed in human lung cancer cell lines and tumor tissues, but not in normal lung (29). More importantly, we have shown Sp17- loaded DCs activate CTLs capable of eliciting antitumor responses, in vitro (29). Finally, Dadabayev et al have reported the safety and clinical response of Sp17- pulsed DCs in patients with MM and ovarian cancer, validating the clinical potential of this protein as an immunotherapeutic target (30). Taken together, these findings suggest the feasibility of exploiting Sp17 -pulsed DC immunotherapy as a promising treatment option for patients with both hematologic and SM. AKAP-4 A-kinase anchori ng protein 4 (AKAP -4) is a member of a growing family of scaffolding proteins involved in the control of signal transduction by targeting cyclic adenosine monophosphate- dependent protein kinase -A, and directing its actions (31, 32) . We have shown that AKAP -4 is expressed in lung cancer and MM cells, at both the transcriptional KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 10 of 47 and the protein level, with no evidence of expression in human normal tissues, other than the testis (29, 33) . The lack of expression in normal tissues and the presence of AKAP -4 antibodies in lung cancer and MM patient sera supports the protein’s immunogenicity and indicates AKAP -4 is a novel T APA in these two malignancies. Additionally, we have also demonstrated AKAP -4 serves as a marker of disease status in a murine model of MM, supporting its importance in the biology of this disease (34). Thus, our findings suggest AKAP -4 is a potential target for developing specific immunotherapeutic strategies against MM, lung cancer and possibly other SM ( 29). Ropporin Ropporin is a rhophilin- associated protein normally expressed in the inner fibrous sheath of sperm flagella. Ropporin has previously been found to interact with other fibrous sheath proteins, including Sp17 and AKAP -110, suggesting a common or related biological function. A study by Li et al has demonstrated a very restricted RNA expression of ropporin in normal tissues, with the exception of testicular and fetal liver tissue (35). Ropporin expression was also detected in tumor cells derived from the bone marrow in 6 of 16 (37.5%) patients with MM, 6 of 14 (43%) cases of CLL and 2 of 11 (18%) cases of acute myeloid leukemia. No ropporin transcripts were detected in the peripheral blood mononuclear cells of 17 healthy donors. Importantly, these investigators detected high titers of antibodies against ropporin in 8 of 30 MM (26.7%), 7 of 24 AML (29.2%), 18 of 31 chronic lymphocytic leukemia (CLL) (58.1%), 9 of 27 chronic myelogenous leukemia (CML) (33.3%) and 1 of 3 acute lymphoblastic leukemia (ALL) (33.3%), compared to healthy donors. The presence of ropporin antibodies in patients with a variety of malignancies indicates this CTA is a highly immunogenic p rotein. Taken together, these findings support the notion that ropporin is a tumor -restricted CTA with a potential role in the biology of certain neoplasms. The restricted expression of ropporin in neoplastic cells, testes and fetal liver, makes it a suitable candidate as a target for immunotherapy including DC vaccine applications. PTTG -1 PTTG -1 is a novel oncogene involved in transcriptional and cell cycle regulation with expression in the normal testis and thymus (36). PTTG -1 has been shown to be highly expressed in different hematologic malignancies (HM) including promyelocytic leukemia (PML) cell line HL -60, CML cell line K -562, ALL cell line MOLT -4 and Burkitt's lymphoma cell line Raji (37). PTTG -1 has also been shown to be associated with tumorigenesis, angiogenesis and cancer progression, making it a logical therapeutic target (36). We and others have found PTTG -1 is expressed at the transcriptional level in MM, with PTTG -1 being expressed in 63% of MM patients and 66% of human MM cell lines studied, but not in normal tissues (38). We also documented cytoplasmic and surface PTTG -1 expression in plasma cells from MM patients supporting PTTG -1 potential role as a therapeutic target in patients with HM. More recently, we have also demonstrated PTTG -1 expression in lung cancer tissues and cell lines and showed PTTG -1-loaded DCs KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 11 of 47 can activate CTL -mediated lysis of human lung cancer cells, i n vitro (29). Therefore, our data indicates the suitability of using PTTG -1 as a potential target for immunotherapy in both HM and SD. Span- xb Span -xb is a novel CTA expressed in CML and other neoplasms. Using RT -PCR, we have detected Span -xb transcripts in 20% of MM patients, 33% of patients with CLL, 29% of CML patients and 50% of patients with AML. In contrast, Span- xb expression was not detected in peripheral blood or bone marrow samples from healthy donors (39). Importantly, span- xb gene expression has also been found in a variety of SM, including melanoma and carcinomas of the lung, colon and breast, making it a target for immunotherapeutic interventions ( 40). Her-2/neu HER -2/neu is a trans -membrane tyrosine -kinase involved in aberrant signal transduction in a variety of neoplasms (41, 42) . HER-2/neu amplification has been demonstrated in certain HM and its functional inhibition, using anti -sense oligonucleotides, results in a reduced tumor cell proliferative rate. The observation that Her -2/neu is expressed at very low levels in normal tissu es and preferentially expressed in neoplastic cells, suggest it could serve as an immunotherapeutic target in HER -2/neu- expressing SM. In fact, Scardino et al have demonstrated HLA -restricted CTL activation by high several high affinity HER -2/neu peptides capable of HLA -restricted killing of neoplastic cells of diverse origin (43). Thus, specific Her -2/neu peptides may serve as good candidates for immunotherapy in HER-2-expressing SM. HM1.24 The HM1.24 protein is a novel, 29- 33 kDa membrane glycoprotein expressed in mature B - cells. We have proposed HM1.24 as a new antigen for CTLs activation against MM ( 44). HM1.24 expression has been found in all five human MM cell lines assayed, as well as in mature, Ig -secreting B -cells (plasma cells and lymphoplasmacytoid cells), but not in non- B-Cells in the periphera l blood, bone marrow, liver, spleen, kidney, or heart of normal individuals or patients with non- plasma -cell-related malignancies. Thus, HM1.24 protein represents a specific marker of late- stage B -cell maturation and may potentially serve as a target antig en for the development of immunotherapeutic strategies specific against MM. HM1.24 is also expressed in SM including brain tumors, renal, hepatocellular, breast, ovarian, and breast carcinomas, with some expression in a few normal organs including liver a nd kidney (45). Although HM1.24 function is unknown at this time, its promise as a therapeutic target has been demonstrated using a specific HM1.24 monoclonal antibody (MoAb) (46). KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 12 of 47 NY-ESO-1 NY-ESO -1 is one of the most immunogenic tumor antigens known to date. Spontaneous humoral and cellular immune responses against NY -ESO -1 are detected in a substantial proportion of patients with NY -ESO -1 expressing malignancies and NY -ESO -1 antibody titers correlate with clinical development of disease (47). Moreover, the development of NY-ESO -1 serum antibody is associated with detectable NY- ESO -1-specific CD8+ T cell reactivity, suggesting this antigen is an excellent immu nogen and potential therapeutic target, in vivo (48). MAGE -1 MAGE -1 is expressed in hematologic malignancies, including human MM cell lines and malignant plasma cells, as well as melanomas (49, 50) . Both RNA and protein expression has been demonstrated in MM cells, but not in polyclonal, reactive plasma cells. Moreover, anti-MAGE -1 HLA -A1 cytotoxic T lymphocytes can efficiently kill MAGE -1 HLA -A1 expressing MM and melanoma cells, suggesting MAGE -1 represents a specific and potential immunotherapeutic target for patients with these malignancies. Using an HLA binding prediction algorithm, we have identified peptides, within the sequence of the above -mentioned antigens, predicted to have high binding affinity to HLA - class I and class II molecules. Peptide sequences from each antigen were linked together using the furin- sensitive linker, RVKR. This linker is used to connect peptides with different HLA restrictions to form a unique long peptide, and it was shown to be safe and effective in previous clinical trials linking the MAGE -A3 or human papillomavirus (HPV) - 16 derived peptides, and the a “penetrin” peptide sequence derived from HIV -TAT (51, 52) (IND#10927, #NCT00257738). The rationale for using long peptides (synthetic long peptides, SLP) is based on the evidence that dendritic cells present SLP better than whole proteins, and that the anti- SLP immune repose lasts longer than that of short peptides ( 53, 54). The SLP sequences are as follows (the linker peptide, RVKR , is evidenced in bold ). 1) SP17 SP17 - peptide A IPQGFGNLLEGLTREIL RVKR DNIPAFAAAYFESLLE RVKR KTNFDPAEW SP17 -peptide B KEEETSVTILDSSEEDKEKEEVAAVKIQAAFRGHIAR RVKR AKKMKTNSL 2) AKAP4 AKAP4- peptide A MMAYSDTTMMSDDIDWL RVKR YALGFQHALSPSTST RVKR YADQVNIDYLMNRPQNLRLEM RVKR CSID DLSFYVNRLSSLVIQMA AKAP4- peptide B FLYSELSNK RVKR PASVVLKRVLLRHTKEIRVKR MEAMLKRLVSALIGE RVKR QSLSYASLK KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 13 of 47 AKAP4- peptide C GEHILKEGL RVKR MSNIVLMLI RVKR WIAASQFNVPMLY RVKR EAVGKVARK 3) PTTG1 PTTG1 - peptide A KLGSGPSIKRVKR RSQVSTPRFRVKR LPKATRKALGTVNRATEK PTTG1 - peptide B FFPFNPLDFRVKR EHQIAHLPLRVKR RELEKLFQLGPPSPVKMRVKR ILSTLDVELPPV 4) ROPPORIN -1 ROPN1 - peptide A DLIQWAADYFEAL RVKR LLKILHSQVAGRLIIRAEELAQMW ROPN1 - peptide B IEWLKFLALACSALGVTIT RVKR SPRIPFSTFQFLYTYIAKVDGEI RVKR HVSRMLNYM 5) Spanx -B1 SPNXB1 SESSTILVVRYRRNVKRTS RVKR MEEEEFIEI 6) NY -ESO-1 NYESO1 - peptide A APRGPHGGA RVKR RLLEFYLAMPFATPM RVKR SLAQDAPPL NYESO1 - peptide B ILTIRLTAADHRQLQLSISSCLQQLSLLMWI RVKR FLPVFLAQPPSGQRR 7) MAGE -1 MAGE1 - peptide A SAFPTTINF RVKR ILESLFRAVITKKVADLVGFL RVKR IMPKTGFLI MAGE -1 peptide B EIWEELSVM RVKR AETSYVKVLEYVIKVSARVRFFFPSLREAAL 8) Her2/Neu Her2/Neu peptide A CRWGLLLALRVKR HLDMLRHLY RVKR LELTYLPTNA SLSFL RVKR QLFEDNYAL Her2/Neu peptide B ETLEEITGY RVKR SVFQNLQVIRGRILH RVKR RELGSGLAL RVKR FRNPHQALL RVKR LTSIISAVVRVKR LIKRR QQKIRKYTMRRLLQ Her2/Neu peptide C SGAFGTVYK RVKR VMAGVGSPY RVKR MQIAKGMSY RVKR GKVPIKWMALESILRRRFT RVKR SYGVTVWE LRVKR AARPAGATL RVKR PAFDNLYYW 9) HM1.24 KRCKLLLGI RVKR PLIIFTIKANSEACR RVKR HTVMALMASLDAEKA RVKR KLQDASAEV RVKR VLSVRIADK Being more specific, and potentially less toxic than chemotherapy, immunotherapeutic strategies, such as TAPA -pulsed DC vaccination, may prove an ideal treatment for patients with a variety of SM. In fact, such an approach has recently gained FDA approval for KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 14 of 47 patients with advanced prostate cancer (55). Therefore, studies using novel TAPAs are clearly warranted in patients with limited therapeutic options, such as those with progressive and/or refractory SM. A promising way of optimizing the efficacy of therapeutic vaccines would be the inhibition of suppressive T -cell populations, such as Tregs. It has been recognized for many years that cyclophosphamide (CYP) can exert both cytotoxic and immunosuppressive effects, depending on the dose used. For example, studies have shown that low -dose cyclophospha mide (CYP) decreases Treg number and functionality (56). Greten and colleagues evaluated single-agent CYP doses of 150, 250, and 350 mg/m 2 in patients with hepatocellular carcinoma and reported that the two (2) lower doses induced a decrease in the absolute and relative frequency of Tregs in the blood of patients, and the 250 mg/m 2 dose impaired suppressor function and showed decreased Treg frequency up to day 71. Alpha- fetopro tein–specific T -cell responses were also induced in the lower treatment arms (57). In a different study, breast cancer patients received CYP, 50 mg orally daily for 3 months. Tregs were reduced within 14 days of treatment and remained decreased until day 42, returning to pretreatment levels by day 84. Interestingly, endogenous breast tumor – reactive T cells were detected in 27% of patients before CYP treatment and increased to 73% on day 14, 80% on day 42, and 88% on day 84, indicating enhanced T -cell function after the use of metronomic doses of CYP (58). More recently, the use of metronomi c CYP combined with active immunotherapy has been reported (59). In this study, patients with advanced solid tumors were treated with 3 different regimens of low -dose CYP in combination with an oncolytic adenovirus. CYP was given either as oral metronomic (50 mg/day), a single intravenous (i.v.) injection (1,000 mg), or both. Metronomic CYP was given starting 1 week before the adenovirus, and i.v. cyclophosphamide was given 1 hour prior to the adenovirus. All CYP regimens resulted in hi gher rates of disease control when compared with the rates for the adenovirus vaccine only, and the metronomic groups were most effective in decreasing Treg numbers. Based on these encouraging results numerous studies are in progress combining metronomic doses of CYP with active vaccination strategies (ClinicalTrials.gov) for a variety of cancers. For an excellent discussion on the role of low -dose CYP as a suppressor of Treg activity and its potential in cancer immunotherapy, see the review by Le and Jaffee (60). Two additional strategies to optimize the efficacy of anti- tumor cellular vaccines would be to improve the ex-vivo generation of DCs with an immunogenic phenotype and to select appropriate adjuvant molecules or cytokines to enhance DC migration and activation, in vivo. For example, the use of type I interferons and Toll -like receptor agonists to induce DC maturation ex-vivo have been shown to stimulate generation of immunogenic, rather than tolerogenic, DCs ( 6, 61). Activation of Toll -Like Receptor 7 (TLR7) has been shown to improve the survival and immunogenicity of DC (62-64) (#NCT01792505). Additionally, topical usage of the imiquimod cream meaningfully improved DC migration and increased numbers of emigrated DCs. By contrast, intradermal in jection of soluble imiquimod or the TLR7/8 KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 15 of 47 ligand R848 did not result in the same effect (65). Of note, TLR7 adjuvant is available as a topical cream, i.e. Imiquimod (Alda ra cream), with evident advantages over other classical DC adjuvants such as GM -CSF, which requires injections ( 66). In this phase I/II study we will examine the feasibility, toxicity, immune response and antitumor activity of TAPA -pulsed DC therapy in patients with progressive and/or refractory SM. To improve the efficacy of this strategy, selected TAPAs will be used to pulse DCs ex-vivo, in the presence of a highly immunogenic maturation cocktail (9, 12, 19, 20). Patients will also be treated with low -dose CYP prior to each DC vaccination, in an attempt to decrease the number and activity of Tregs, and topical Imiquimod will be administered following each DC vaccination, in order to optimize immune responses in patients with relapsed/refractory SM. A similar strategy has r ecently been safely explored by others in patients with refractory SM (9). 2.0 HYPOTHESIS AND O BJECTIVES 2.1 Hypothesis We hypothesize that treatment of patients with progressive and/or refractory SM, without available, potentially curative therapeutic options, and whose tumor cells express at least one (1) TAPA of a defined panel of TAPAs, using low -dose CYP followed by an autologous, monocyte -derived, TAPA -pulsed DC vaccine and topical Imiquimod , will result in TAPA -specific CD4+ T -cell and CD8+ CTL responses without significant toxicities. We also hypothesize CD4+ T -cell and CD8+ CTL responses generated against specific TAPAs may translate into clinical antitumor activity. 2.2 Primary Objective: Phase I To determine the toxicity of low-dose CYP followed by TAPA-pulsed DC therapy and topical Imiquimod , in patients with progressive and/or refractory SM. 2.3 Secondary Objectives: Phase II To determine immune responses associated with low-dose CYP followed by TAPA- pulsed DC therapy and topical Imiquimod , in patients with progressive and/or refractory SM. 3.0 STUDY DESIGN 3.1 Study Population 3.1.1 Number and Characteristics of Patients Enrolled 1. The study population will be drawn from patients at various institutions in USA following contractual agreements with Kiromic . KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 16 of 47 2. There will be no patient restrictions based on race or gender. 3. Up to six (6) subjects may be enrolled and receive DC vaccination to evaluate toxicity of the proposed vaccination strategy (Phase I stage). 4. Up to an additional eleven (11) patients, for a total of seventeen (17) patients, may be enrolled for determination of immune efficacy (Phase II stage), assuming no overt toxicity is encountered during the safety evaluation. 3.2 Eligibility Criteria Patients must ha ve baseline evaluations performed prior to administration of the first dose of study vaccine and must meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule, required evaluations, and all regulatory requirements for informed consent. The written informed consent must be obtained from the patient prior to enrollment. The following criteria apply to all patients enrolled on the study unless otherwise specified. 3.2.1 Inclusion Criteria 1. Ability to provide informed consent. 2. Patients with histologically proven progressive and/or refractory SM, s/p conventional salvage therapy , completed at least 3 weeks prior to study vaccination, will be eligible for enrollment. 3. Expression of one (1) or more of the following TAPAs: Sp17, AKAP -4, Ropporin, PTTG -1, Span- xb, Her -2/neu, HM1.24, NY -ESO -1 and MAGE -1, by either RT - PCR and/or immunocytochemistry, Western blotting or ELISA, in neoplastic cells. For HER -2/neu expression, positive FISH results are acceptable. 4. Presence of measurable or evaluable disease. 5. Patients must not have any active infectious process. 6. Patients must not have a history of HIV, or active Hepatitis A, B, or C. 7. Patients must not be receiving active immunosuppressive therapy. 8. Patients must have discontinued systemic cytotoxic or radiation therapy at least three (3) weeks prior to vaccination and toxicities from previous therapies must be grade 1 or less . All other FDA approved forms of antineoplastic therapy are allowed such as immunotherapy, targeted therapies, or hormonal therapies (67, 68). 9. Patients may not have any known allergy to CYP and/or Imiquimod . 10. Patients mu st 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. KIROVAX 003 Date: August 22, 2018- Version 00 7 CONFIDENTIAL Page 17 of 47 11. Adequate renal and hepatic function (creatinine ≤ 2.0 mg/dl, bilirubin ≤ 2.0 mg/dl, AST and ALT ≤ 4X upper limit of normal range). 12. Adequate hematologic function (Platelets ≥ 60,000/mm3, lymphocytes ≥ 1,000 mm3, neutrophils ≥ 750/mm3, hemoglobin ≥ 9.0 g/dl). 13. Karnofsky performance status ≥ 70%. 14. Expected survival ≥ 6 months. 15. 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. Birth control methods may include condoms, diaphragms, birth c ontrol 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. Women of reproductive capacity will be required to undergo a urine pregnancy test before completion of the post -screening informed consent process. 3.2.2 Exclusion Criteria 1. Patients without confirmed progressive and/or refractory SM using standard RECIST criteria. 2. Patients without measurable or evaluable disease. 3. Patients receiving cytotoxic or radiation therapy , within three (3) weeks of vaccination. 4. Active immunosuppressive therapy , including non- physiologic systemic steroids (excluding topical , intraocular, inhaled , and intranasal steroids) for any other condition. 5. Persistent fever (>24 hours) documented by repeated measurement or active, uncontrolled infection within 4 weeks of enrollment. 6. Active ischemic heart disease or history of myocardial infarction wit hin six months. 7. Active autoimmune disease, including, but not limited to, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS), Ankylosing Spondylitis (AS), Inflammatory Bowel Disease (IBD), and Rheumatoid Arthritis (RA). 8.