A Personalized Neoantigen Cancer Vaccine in Treatment Naïve, Asymptomatic Patients With IGHV Unmutated CLL.

Inclusion Criteria:

• Diagnosis of CLL as per IWCLL 2018 criteria

• Patient's CLL must have an unmutated immunoglobulin heavy chain variable (IGHV)region gene, defined as < 2% mutated compared to germline.

• Patient must have had no history of CLL-directed therapy due to meeting IWCLL 2018criteria; no present indication for treatment by iwCLL 2018 criteria; and in theopinion of the treating investigator be anticipated not to require CLL-directedtreatment within the next 6 months.

• Patient must have measurable disease (absolute lymphocyte count > 10K/uL or totalwhite blood cell count ≥ 20K/uL of peripheral blood).

• Patient must have had at least two other absolute lymphocyte counts (ALC) measuredsince diagnosis of CLL that are at least 2 weeks apart and at least 2 months priorto the one used for initial registration.

• Age ≥ 18 years.

• ECOG performance status 0 or 1

• Participants must have normal organ and marrow function as defined below:

• total bilirubin within normal institutional limits

• AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

• absolute neutrophil count ≥1000 cells/μL

• The effects of NeoVax and poly-ICLC on the developing human fetus are unknown. Forthis reason, women of childbearing potential (WOCBP) must have a negative pregnancytest (minimum sensitivity 25 IU/L or equivalent of HCG) before entry onto the trialand within 7 days prior to start of study medication. It is the investigators'responsibility to repeat the pregnancy test should start of treatment be delayed.

• Female patients enrolled in the study, who are not free from menses for >2 years,post hysterectomy / oophorectomy, or surgically sterilized, must be willing to useeither 2 adequate barrier methods or a barrier method plus a hormonal method ofcontraception to prevent pregnancy or to abstain from sexual activity throughout thestudy, starting with visit 1 through 4 weeks after the last dose of study therapy.Approved contraceptive methods include for example; intra uterine device, diaphragmwith spermicide, cervical cap with spermicide, male condoms, or female condom withspermicide. Spermicides alone are not an acceptable method of contraception.

• Patient is agreeable to allow tumor (from peripheral blood) and normal tissue (fromsaliva) samples to be submitted for complete exome and transcriptome sequencing.

• Ability to understand and the willingness to sign a written informed consentdocument.

• At least 7 immunizing peptides can be designed.

• Continue to meet inclusion and exclusion criteria for Screening Registration.

Exclusion Criteria:

• Prior therapy for CLL that met IW-CLL treatment criteria, including chemotherapy,targeted therapies (e.g. that antagonize B cell receptor signaling), orimmunotherapy (including but not limited to monoclonal antibodies); or radiotherapyor hormonal therapy within the last 2 years of screening registration.

• Participants who are receiving any other investigational agents.

• Previous bone marrow or stem cell transplant

• Concomitant therapy with immunosuppressive or immunomodulatory agents; chronic useof systemic corticosteroids. Previous history of corticosteroid use is acceptable.Use of corticosteroids after initial registration is acceptable if tapered at leastone week before NeoVax administration.

• Use of a non-oncology vaccine therapy for prevention of infectious diseases within 2weeks of any NeoVax administration.

• History of severe allergic reactions attributed to any vaccine therapy for theprevention of infectious diseases.

• Participants who have never received the tetanus vaccine.

• Active, known, or suspected autoimmune disease or immunosuppressive conditions withthe exception of vitiligo, type 1 diabetes, residual autoimmune-relatedhypothyroidism requiring hormone replacement, or psoriasis not requiring systemictreatment.

• Uncontrolled autoimmune cytopenia.

• No lymph node > 5 cm by CT scan (measured as long axis).

• Del(17p) by fluorescence in situ hybridization in ≥ 10% of CLL cells analyzed

• Any documented transformation of CLL (i.e. Richter's Syndrome).

• Lymphocyte doubling time (LDT) < 6 months in patients with WBC > 30,000/uL. Factorscontributing to lymphocytosis other than CLL (e.g. infections) should be excludedwhen calculating the LDT1.

• Serum immunoglobulin level <400 mg/dL or currently requiring chronic intravenousimmunoglobulin G (IVIG)

• Known chronic infections with HIV, hepatitis B or C (see Study Calendar in Section 10 for screening assays).

• Has received prior therapy with an anti-PD1, anti PD-L1, or anti PD-L2 agent.

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia.

• Any underlying medical condition, psychiatric condition or social situation that inthe opinion of the investigator would compromise study administration as perprotocol or compromise the assessment of AEs.

• Pregnant women are excluded from this study because personalized neoantigen peptidesand poly-ICLC are agents with unknown risks to the developing fetus. Because thereis an unknown but potential risk of adverse events in nursing infants secondary totreatment of the mother with personalized neoantigen peptides and poly-ICLC, nursingwomen are excluded from this study.

• Individuals with history of an invasive malignancy are ineligible except for thefollowing circumstances: a) individuals with a history of invasive malignancy areeligible if they have been disease -free for at least 3 years and are deemed by theinvestigator to be at low risk for recurrence of that malignancy; b) individualswith the following cancers are eligible if diagnosed and treated: carcinoma in situof the breast, oral cavity or cervix and basal cell or squamous cell carcinoma ofthe skin; c) individuals with prostate cancer managed with active surveillance thatis not expected to limit their survival to <10 years.

• Participants with known CNS involvement should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to poly-ICLC.

• HIV-positive participants on combination antiretroviral therapy are ineligiblebecause assessment of immunologic endpoints may be confounded by HIV-inducedalterations in patient immune status and function. Appropriate studies will beundertaken in participants receiving combination antiretroviral therapy whenindicated