5. 2 De ter mi n ati o n of t he rel ati o ns hi p bet w ee n M D S C n u m bers a n d a nti -p 5 3 T cell res p o nses. Bl o o d ( 7 s o di u m he pari n vac utai ner t u bes, 1 0 ml eac h a n d 1 re d t o p t u be) will be o btai ne d fr o m e ac h patie nt o n s e veral differ e nt occasi o ns. T he P B M C will be a nal yze d b y fl o w c yt o metr y f or t he prese n ce of M D S Cs, a n d t he a bs ol ute n u m bers as well as rati os will be deter mi ne d. P B M C fr o m eac h sa m ple will be stai ne d i m me diatel y t o e v al uate t he pres e nce of M D S C. T he f oll o wi n g criteri a will be use d t o e val uate M D S C b y fl o w c yt o metr y: 1. Li n ( C D 3, C D 1 4, C D 1 9, C D 5 6) ne gati ve, H L A- D R -, C D 3 3 +; 2. M D S C: C D 1 1 b + C D 1 4- C D 3 3 +; 3. P M N- M D S C: C D 1 1 b + C D 1 4- C D 3 3 + C D 1 5 +; 4. M- M D S C: C D 1 1 b + C D 1 4- C D 3 3 + C D 1 5-; 5. M- M D S C: C D 1 4 + H L A- D R -/l o; Protocol: Version 8.0. September 19 , 2018 Page | 46 7.1.5.3 Analysis of other Immune Cells Correlative analysis will be performed on the peripheral blood mononuclear cells (PBMC) of all the patients enrolled in the study. This will include flow cytometry based assessment of presence of suppressive cell types such as myeloid -derived suppressor cells (MDSC) and Tregs. In addition, we will determine expression of activation and resistance markers in lymphocytic lineages, including T cells, by flow cytometry and gene expression studies. 7.1.5.4 Immuno histochemical Stains Archival or fresh paraffin -embedded tissue blocks containing formalin- fixed tumor or needle aspirate slides will be obtained for evaluation of the expression of p53 and PD -L1 using IHC methods with commercial antibodies. Paraffin block s may be processed according to standard institutional protocols. If blocks are unavailable, 15 unstained slides are acceptable alternatives. This IHC scores will be correlated with the clinical efficacy endpoints and the blood surrogate biomarkers. Approx imately half of the patients are expected to contribute with an archival tumor biopsy. Sections of formalin -fixed, paraffin -embedded tissue from the SCLC will be cut and stained with the respective antibodies against PD -L1 (TBD) and p53 (DO7, DAKOcytomati on, 1:50). In brief, the slides will be immersed in citrate buffer solution for antigen retrieval and boiled in microwave for 10 min and washed in buffer solution (TBS). They will be incubated with primary antibody for 1 hr at room temperature and then washed in TBS. After 1 hr of incubation in the secondary antibody, the sections will be incubated with streptavidin- biotin - complex (DAKOcytomation). Appropriate positive and negative controls will be used. Results of IHC staining will be evaluated in the following 2 ways: (1) For estimation of positive reaction, only the strongly stained nuclei are counted as a percentage of all tumor nuclei. Less than 5% are estimated as negative. Samples with greater than 5% of cells exhibiting strong nuclear staining would be considered positive. (2) protein staining is scored, taking into account percentage of positive cells (from 1 to 100%) and intensity of staining (from 1 to 3), as compared with the protein intensity level 3 of the background lymphocytes. Total score is established by multiplying the percentage by intensity, giving scores of 0 to 300. Final scores of 1, 2, and 3 are given for total scores of 10- 50, 50- 100, and 100-300, respectively. 7.1.6 Visit Requirements Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure -related details are provided above in Section 7.1 - Trial Procedures. 7.1.6.1 Screening Screening evaluation requirements are outlined in Section 6.0 - Trial Flow Chart. 7.1.6.1.1 Screening Period Defined in Section 6.0 - Trial Flow Chart 7.1.6.2 Treatment Period Defined in Section 6.0 - Trial Flow Chart Protocol: Version 8.0. September 19 , 2018 Page | 47 7.1.6.3 Post-Treatment Visits Defined in Section 6.0 - Trial Flow Chart 7.1.6.3.1 Safety Follow- Up Visit The mandatory Safety Follow -Up Visit should be conducted approximately 30-45 days after the last dose of trial treatment or before the initiation of a new anti -cancer treatment, whichever comes first (End of trial, EOT). All AEs that occur prior to the Safety Follow -Up Visit should be recorded. Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0- 1 or until the beginning of a new anti -neoplastic therapy, whichever occurs first. SAEs that occur within 90 days of the end of treatment or before initiation of a new anti -cancer treatment should also be followed and recorded. Subjects who are eligible for retreatment with Ipi-Nivo or Nivo (as described in Section 7.1.5.5) may have up to two safety follow -up visits, one after the Treatment Period and one after the Second Course Phase. 7.1.6.4 Follow- up Visits Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow -Up Phase and should be assessed every 6 weeks ( 42 ± 7 days) by radiologic imaging to monitor disease status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days). Every effort should be made to collect information regarding disease status until the start of new anti- neoplastic therapy, disease progression, death, end of the study or if the subject begins retreatment with Ipi-Nivo or Nivo as detailed in Section 7.1.5.5. Information regarding post -study anti -neoplas tic treatment will be collected if new treatment is initiated. Subjects who are eligible to receive retreatment with Ipi-Nivo or Nivo according to the criteria in Section 7.1.5.5 will move from the follow -up phase to the Second Course Phase when they experience disease progression. 7.1.6.4.1 Survival Follow- up Once a subject experiences confirmed disease progression or starts a new anti -cancer therapy, the subject moves into the survival follow -up phase and should be contacted by telephone every 12 weeks to asses s for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 7.1.6.5 Second Course Phase (Retreatment Period) Subjects who stop Ipi-Nivo or Nivo with SD or better may be eligible for up to one year of additional Ipi-Nivo or Nivo therapy if they progress after stopping study treatment. This retreatment is termed the Second Course Phase of this study and is only available if the study remains open and the subject meets the following conditions: • Either o Stopped initial treatment with Ipi-Nivo or Nivo after attaining an investigator - determined confirmed CR according to RECIST 1.1 OR o Had SD, PR or CR and stopped Ipi-Nivo or Nivo treatment after 6-12 months of study therapy for reasons other than disease p rogression or intolerability Protocol: Version 8.0. September 19 , 2018 Page | 48 AND • Did not receive any anti -cancer treatment since the last dose of Ipi -Nivo or Nivo • Has a performance status of 0 or 1 on the ECOG Performance Scale • Demonstrates adequate organ function as detailed in Section 5.1.2 • Female sub ject of childbearing potential should have a negative serum or urine pregnancy test within 72 hours prior to receiving retreatment with study medication. • Female subject of childbearing potential should be willing to use 2 methods of birth control or be s urgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication (Reference Section 5.7.2). Subjects of child bearing potential are those who have not been surgically sterilized or have been free from menses for > 1 year. • Male subject should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. • Does not have a history or current evidence of any condition, therapy, or laboratory abnormality that might interfere with the subject’s participation for the full duration of the trial or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Subjects who restart treatment will be retreated at the same dose and interval as per the original treatment schedule in section 5.2.2. Treatment will be administered for up to one additional year. Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 7.2 Assessing and Recording Adverse Events An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol - specified procedure, whether or not considered related to the medicinal product or protocol - specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associ ated with the use of the investigational product, is also an adverse event. Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered adverse events. Examples of this may include, but are not limited to, teething, typical crying in infants and children and onset of menses or menopause occurring at a physiologically appropriate time. BMS product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol -specified procedure, whether investigational (including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by BMS for human use. Adverse events may occur during the course of the use of BMS product in clinical trials or within the follow -up period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal. Protocol: Version 8.0. September 19 , 2018 Page | 49 Adverse events may also occur in screened subjects during any pre -allocation baseline period as a result of a protocol -specified intervention, including washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. Progression of the cancer under study is not considered an adverse event unless it is considered to be drug related by the investigator. All adverse events will be recorded from the time the consent form is signed through 30 days following cessation of treatment and at each examination on the Adverse Event case report forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1 and section 11.7 BMS guidelines for Adverse Event Reporting. 7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor and to BMS For purposes of this trial, an overdose of Ipi-Nivo or Nivo will be defined as any dose of 2400 mg or greater (≥5 times the indicated dose). No specific information is available on the treatment of overdose of IPI-NIVO OR NIVO. Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with (“results from”) the overdose of a BMS product , the adverse event(s) is reported as a seriou s adverse event, even if no other seriousness criteria are met. If a dose of BMS ’s product meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.” All reports of overdose with and without an adverse event must be reported within 24 hours to the Sponsor and within 2 working days hours to BMS 7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to BMS Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 120 days of completing the trial completing the trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier . All subjects and female partners of male subjects who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, Protocol: Version 8.0. September 19 , 2018 Page | 50 miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported within 24 hours to the Sponsor and within 2 working days to BMS (see section 11.7) 7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to BMS 7.2.3.1 Serious Adverse Events A serious adverse event is any adverse event occurring at any dose or during any use of BMS ’s product that: • Results in death; • Is life threatening; • Results in persistent or significant disability/incapacity; • Results in or prolongs an existing inpatient hospitalization; • Is a congenital anomaly/birth defect; • Is a new cancer (that is not a condition of the study); • Is associated with an overdose; • Is another important medical event Refer to Table 6 for additional details regarding each of the above criteria. Any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study that occurs to any subject from the time the consent is signed through 90 days following cessation of treatment, or the initiation of new anti- cancer therapy, whichever is earlier, whether or not related to BMS product, must be reported within 24 hours to the Sponsor and within 2 working days to BMS . Non-serious Events of Clinical Interest will be forwarded to BMS and will be handled in the same manner as SAEs. Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to BMS product that is brought to the attention of the investigator at any time outside of the time period specified in the previous paragraph also must be reported immediately to the Sponsor and to BMS . SAE reports and any other relevant safety information are to be forwarded to the BMS A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. Investigators will cross reference this submission according to local regulations to the BMS Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally investigators will submit a copy of these reports to BMS at the time of submission to FDA. All subjects with serious adverse events must be followed up for outcome. Protocol: Version 8.0. September 19 , 2018 Page | 51 7.2.3.2 Events of Clinical Interest Selected non -serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 24 hours to the Sponsor and within 2 working days to BMS (see section 11.7) Events of clinical interest for this trial include: 1. an overdose of BMS product, as defined in Section 7.2.1 - Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or abnormal laboratory results. 2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of protocol -specified laboratory testing or unscheduled laboratory testing.* *Note: Thes e criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology. The trial site guidance for assessment and follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent). Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and subjects should be asked for signs and symptoms suggestive of an immune -related event. Subjects who develop an ECI thought to be immune -related should have additional testing to rule out other etiologic causes. If lab results or symptoms indicate a possible immune -related ECI, then additional testing should be performed to rule out other etiologic causes. If no other cause is found, then it is assumed to be immune- related. 7.2.4 Evaluating Adverse Events An investigator who is a qualified physician will evaluate all adverse events according to the NCI Comm on Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which changes CTCAE grade over the course of a given episode will have each change of grade recorded on the adverse event case report forms/worksheets. All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 7.2.5 Sponsor Responsibility for Reporting Adverse Events All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations. 7.3 Safety Stopping Criteria The purpose of safety stopping criteria is to control the number of subjects put at risk, in the event that early experience uncovers important safety problems. The event I have chosen to utilize as our safety target or endpoint is: “ grade 4 adverse events that are at least possibly related to the investigational treatment ”. Protocol: Version 8.0. September 19 , 2018 Page | 52 Based on our SCLC historical control population treated with the ipilimumab-nivolumab combination86, grade 3- 4 treatment related adverse events occurred in 30% of patients. Given that an additional investigational agent /treatment (vaccine) is being added, we are willing to accept similar to slightly higher frequency of adverse events. Thus, the protocol we will abide by the following study stopping criteria: 7.3.1 We will first accrue 10 patients to the study. a. If at the end of the first 3 vaccine administrations, the event occurs in 4 or less patients, we will accept the safety profile of our combination to be comparable to that of our SCLC historical control 86 and the regimen will be consider safe for further treatment and the study will open to accrual unrestricted, until study completion b. If at the end of the first 3 vaccines administrations, the event occurs in 5 or 6 patients, we will accrue an additional 10 patients before the study opens to accrual unrestricted, until study completion. c. If at the end of the fi rst 3 vaccine administrations, the event occurs in 7 or more patients, we will consider our treatment combination unsafe and the study will be closed. 7.3.2 In case that an additional 10 patients need to be accrued (see above item 1b) d. If at the end of the first 3 vaccine administrations, the event occurs in 4 or less patients, we will accept the safety profile of our combination to be comparable to that of our SCLC historical control 86 and the regimen will be consider safe for further treatment and the study will open to accrual unrestricted, until study completion e. If at the end of the first 3 vaccine administrations, the event occurs in more than 4 patients, we will c onsider our treatment combination unsafe and the study will be closed. Protocol: Version 8.0. September 19 , 2018 Page | 53 Table 6 Evaluating Adverse Events An investigator who is a qualified physician, will evaluate all adverse events as to: V4.0 CTCAE Grading Grade 1 Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age -appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life -threatening; hospitalization or prolongation or hospitalization indicated; disabling; limiting self -care ADL. Grade 4 Life threatening consequences; urgent intervention indicated. Grade 5 Death related to AE Seriousness A serious adverse event is any adverse event occurring at any dose or during any use of BMS product that: †Results in death ; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as i t occurred (Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or †Is a congenital anom aly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or Is a new cancer; (that is not a condition of the study) or Is an overdose (whether accidental or intentional). Any adverse event associated with an overdo se is considered a serious adverse event. An overdose that is not associated with an adverse event is considered a non -serious event of clinical interest and must be reported within 24 hours. Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse eve nt when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †). Duration Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units Action taken Did the adverse event cause the BMS product to be discontinued? Relationship to test drug Did the BMS product cause the adverse event? The determination of the likelihood that the BMS product caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available informat ion. The following components are to be used to assess the relationship between the BMS product and the AE ; the greater the correlation with the components and their respective elements (in number and/or intensity), the more likely the BMS product caused the adverse event (AE): Exposure Is there evidence that the subject was actually exposed to the BMS product such as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? Time Course Did the AE follow in a reasonable temporal sequence from admi nistration of the BMS product? Is the time of onset of the AE compatible with a drug -induced effect (applies to trials with investigational medicinal product)? Likely Cause Is the AE not reasonably explained by another etiology such as underlying diseas e, other drug(s)/vaccine(s), or other host or environmental factors Protocol: Version 8.0. September 19 , 2018 Page | 54 Relationship The following components are to be used to assess the relationship between the test drug and the AE: (continued) to BMS product (continued) Dechallenge Was the BMS product discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve?