Phase II, open label, randomized multicenter study to evaluate efficacy and safety of study treatment in previously untreated patients with advanced pancreatic cancer. Patients will receive study treatment for a maximum of 24 months or until progression disease or until unacceptable toxicity. In the experimental arm, patients who discontinue chemotherapy for reasons other than disease progression may continue receiving the remaining study drugs (NLM-001, botensilimab and balstilimab) up to a maximum of 24 months, according to schedule.

Participants will be centrally randomized 1:1 to one of the study arms. Randomization will be stratified according to:

1. ECOG Performance Status (0 vs 1)
2. Presence of liver metastases (yes vs no)

Inclusion Criteria:

1. Investigators must ensure that patients are able to understand the requirements of the study and provide informed consent.

2. Age ≥18 years.

3. Histological or cytological diagnosis of pancreatic adenocarcinoma.

4. Stage IV disease.

5. No prior treatment for advanced disease. Patients who have received chemotherapy for localized disease are eligible if they progress within six months from the last chemotherapy treatment.

6. Measurable disease per iRECIST 1.1 as determined by the investigator.

7. ECOG (Eastern Cooperative Oncology Group) PS 0-1.

8. Sufficient hematopoietic, renal and liver function as defined as:

   • Neutrophil count ≥ 1.5 x 10^9 / L
   • Platelet count ≥ 100 x 10^9 / L
   • Bilirubin ≤ 1.5 x ULN (upper limit of normal)
   • AST and / or ALT ≤2.5 x ULN or ≤5 for patients with liver disease
   • Serum creatinine ≤ 1.5 x ULN

9. Tumor lesion amenable to safe repeated tumor biopsy.

10. Women of child-bearing age and men who wish to participate in the study must agree to use appropriate contraceptive methods from the signing of informed consent until 6 months for women and 3 months for men after discontinuation of the study drug o Adequate contraception includes abstinence, oral contraceptives, transdermal patches, and injections that prolong release of a progestogen (starting at least 4 weeks prior to the administration of the investigational drug), condom or female condom (diaphragm or condom / vaginal) plus spermicide, intrauterine device (IUD), implant or a vaginal ring (placed at least 4 weeks prior to administration of investigational drug) or male partner sterilization (vasectomy with documentation of azoospermia) before the inclusion of the woman in the trial if the male is the only sex partner of the woman (see appendix G).

Exclusion Criteria:

1. Active or uncontrolled infectious disease or serious medical condition that may interfere with the patient's eligibility or treatment.

2. History of psychiatric condition that would compromise the patient's ability to understand or comply with the requirements of the protocol, or the ability to provide informed consent.

3. Concurrent antineoplastic therapy.

4. Prior chemotherapy or chemo-radiation therapy for advanced pancreatic cancer.

5. Prior anti-PD-(L)1 or anti-CTLA-4 as prior therapy(ies).

6. Pregnant or lactating women.

7. History of allergic reactions attributed to compounds of similar chemical structure or similar biological study drug composition.

8. History of life-threatening serious adverse events to Gemcitabine or Nab-Paclitaxel.

9. Patients requiring or being treated with potent CYP3A4 inhibitors and inducers.

10. Other active malignancies undergoing or requiring systemic treatment.

11. History of interstitial lung disease.

12. Subjects with history or presence of a known clotting disorder or difficulty achieving haemostasis will be excluded.

13. Primary or secondary immunodeficiency, including immunosuppressive disease or autoimmune disease (including autoimmune endocrinopathies).

    Note: Subjects with type 1 diabetes, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible. Subjects with Type 2 diabetes mellitus are allowed.

14. Subjects with a known history of human immunodeficiency virus 1 and 2, human T lymphotropic virus 1.

15. Prior treatment with anticancer therapies, immunosuppressive agents, corticosteroids, radiation, investigational drugs or vaccines within the following time intervals before the first dose of study treatment (C1D1):

    (i) Cytotoxic chemotherapy: within 3 weeks prior to C1D1. (ii) Monoclonal antibodies, antibody-drug conjugates or radioimmunoconjugates: within 4 weeks or 5 half-lives, whichever is shorter.

    (iii) Small-molecule targeted therapies, including tyrosine kinase inhibitors: within 2 weeks or 5 half-lives, whichever is shorter.

    (iv) Any other anti-neoplastic therapy (including experimental agents): within 3 weeks, except:

    • Investigational drugs or devices must not have been administered within 21 days or 5 half-lives (whichever is longer).

    • For investigational agents with long half-lives (>5 days), earlier enrolment requires approval by the medical monitor.

      (v) Radiotherapy: - A 1-week washout is permitted for palliative radiation to non-CNS lesions, with medical monitor approval.

    • Patients must not have experienced radiation pneumonitis or be receiving chronic corticosteroids for this condition.

    (vi) Corticosteroids: - No systemic corticosteroids within 7 days, except:

    • inhaled or topical corticosteroids,
    • corticosteroid premedication for contrast allergy,
    • physiologic replacement doses, with medical monitor approval. (vii) Immunosuppressive therapies: - No immunosuppressive treatment within 7 days, except for the permitted corticosteroid uses listed above.

    (viii) SARS-CoV-2 vaccination:

    • No COVID-19 vaccine within 7 days before randomization.
    • When feasible, multi-dose vaccine series should be completed prior to randomization.

16. Has not recovered to grade ≤1 from toxic effects of prior therapy and/or complications from prior surgical intervention before starting therapy.

    Note: Subjects with grade ≤2 neuropathy and alopecia are an exception and may enroll.

17. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful.

18. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of study enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication.

    a. QTcF (QT interval corrected using Fridericia's formula) of > 480 ms.

19. Concurrent participation in other investigational drug trials.

20. Known central nervous system (CNS) involvement as follows:

    • Untreated CNS metastases.
    • Leptomeningeal metastases. Note: Patients may be eligible if CNS metastases have been treated and patients have neurologically returned to baseline (except for residual signs and symptoms related to the CNS treatment).

21. Known to be positive for hepatitis B virus (HBV) surface antigen, or any other positive test for HBV indicating acute or chronic infection. Participants who are receiving or who have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to study enrollment are eligible. Serological testing for HBV at screening is not required.

22. Known active hepatitis C virus (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Participants on or who have received antiretroviral therapy are eligible provided they are virus-free by PCR for at least 6 months prior to study enrollment. Serological testing for HCV at screening is not required.