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 2018 criteria; no present indication for treatment by iwCLL 2018 criteria; and in the opinion of the treating investigator be anticipated not to require CLL-directed treatment within the next 6 months.
* Patient must have measurable disease (absolute lymphocyte count \> 10K/uL or total white blood cell count ≥ 20K/uL of peripheral blood).
* Patient must have had at least two other absolute lymphocyte counts (ALC) measured since diagnosis of CLL that are at least 2 weeks apart and at least 2 months prior to 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. For this reason, women of childbearing potential (WOCBP) must have a negative pregnancy test (minimum sensitivity 25 IU/L or equivalent of HCG) before entry onto the trial and 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 use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from sexual activity throughout the study, starting with visit 1 through 4 weeks after the last dose of study therapy. Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception.
* Patient is agreeable to allow tumor (from peripheral blood) and normal tissue (from saliva) samples to be submitted for complete exome and transcriptome sequencing.
* Ability to understand and the willingness to sign a written informed consent document.
* 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), or immunotherapy (including but not limited to monoclonal antibodies); or radiotherapy or 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 use of systemic corticosteroids. Previous history of corticosteroid use is acceptable. Use of corticosteroids after initial registration is acceptable if tapered at least one week before NeoVax administration.
* Use of a non-oncology vaccine therapy for prevention of infectious diseases within 2 weeks of any NeoVax administration.
* History of severe allergic reactions attributed to any vaccine therapy for the prevention of infectious diseases.
* Participants who have never received the tetanus vaccine.
* Active, known, or suspected autoimmune disease or immunosuppressive conditions with the exception of vitiligo, type 1 diabetes, residual autoimmune-related hypothyroidism requiring hormone replacement, or psoriasis not requiring systemic treatment.
* 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. Factors contributing to lymphocytosis other than CLL (e.g. infections) should be excluded when calculating the LDT1.
* Serum immunoglobulin level \<400 mg/dL or currently requiring chronic intravenous immunoglobulin 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 active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia.
* Any underlying medical condition, psychiatric condition or social situation that in the opinion of the investigator would compromise study administration as per protocol or compromise the assessment of AEs.
* Pregnant women are excluded from this study because personalized neoantigen peptides and poly-ICLC are agents with unknown risks to the developing fetus. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with personalized neoantigen peptides and poly-ICLC, nursing women are excluded from this study.
* Individuals with history of an invasive malignancy are ineligible except for the following circumstances: a) individuals with a history of invasive malignancy are eligible if they have been disease -free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; b) individuals with the following cancers are eligible if diagnosed and treated: carcinoma in situ of the breast, oral cavity or cervix and basal cell or squamous cell carcinoma of the skin; c) individuals with prostate cancer managed with active surveillance that is not expected to limit their survival to \<10 years.
* Participants with known CNS involvement should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to poly-ICLC.
* HIV-positive participants on combination antiretroviral therapy are ineligible because assessment of immunologic endpoints may be confounded by HIV-induced alterations in patient immune status and function. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
