TAC T-cells for the Treatment of HER2-positive Solid Tumors

Inclusion Criteria:

1. Written informed consent.
2. Age ≥ 18 years at the time of informed consent.
3. For Phase 1 and Phase 2:

   * Phase 1 monotherapy (completed): HER2 1+, 2+, 3+ by IHC by central laboratory confirmation
   * Phase 1 combination therapy and Phase 2: HER2 2+, 3+ by IHC and FISH by central laboratory confirmation
4. Histologically confirmed advanced, metastatic, unresectable solid tumors (regardless of PD-L1 expression levels; Phase 1 monotherapy) and histologically confirmed advanced, metastatic, unresectable gastric or esophageal adenocarcinoma (regardless of PD-L1 expression levels for Phase 1 combination therapy and Phase 2) after at least 2 prior lines of therapy (Phase 1) or after at least 2 and no more than 4 prior lines of therapy (Phase 2).

   1. HER2+ incurable malignancies for which no standard-of-care HER2 targeted therapy exists may be enrolled regardless of the number of prior treatment lines, as long as in the opinion of the investigator the subject would be unlikely to tolerate or derive clinically meaningful benefit from other available treatment options.
   2. For breast cancer subjects, both prior lines of therapy must have included HER2-targeted agents per current standard-of-care.
   3. Subjects with solid tumors with genetic alterations and mutations (such as BRAF, BRCA, EGFR mutations, and ALK translocation) where approved targeted therapies were available to their specific cancers must have been previously treated with such approved therapies or refused such approved targeted therapy for their cancers prior to enrollment, or in the opinion of the investigator would be unlikely to tolerate or derive clinically meaningful benefit from these standard-of-care therapies.
5. Measurable disease per RECIST 1.1 at time of enrollment.
6. ECOG performance status of 0 or 1 at Screening.
7. Life expectancy of at least 12 weeks.
8. Adequate organ and bone marrow reserve function.
9. Recovery to Grade ≤1 or Baseline for any toxicities due to previous therapy.
10. Adequate vascular access for leukapheresis.
11. Negative pregnancy test and use of highly effective contraception.
12. Undetectable HBV viral load.
13. HCV viral load is undetectable.

Exclusion Criteria:

1. Intolerant to any component of TAC01-HER2.
2. Prior treatment with any of the following:

   1. Adoptive cell transfer of any kind, including CAR T cells
   2. Gene therapy
3. Investigational medicinal product within 5 half-lives or 21 days prior to leukapheresis, whichever is shorter.
4. Receipt of a live or live-attenuated vaccine within 30 days prior to study treatment.
5. Monoclonal antibody (mAb), including PD-1 and PD-L1, therapies within 21 days prior to leukapheresis.
6. Radiation within 28 days prior to enrollment. Palliative radiation is allowed up to 14 days prior to enrollment if non-irradiated lesions are present.
7. Chemotherapy or targeted small molecule therapy within 14 days prior to leukapheresis, or within 7 days prior to leukapheresis for erlotinib, gefitinib, afatinib, or crizotinib.
8. Colony stimulating factors, including granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, and other hematopoietic cytokines, within 14 days prior to leukapheresis.
9. Immunosuppressive medication within 14 days or corticosteroid treatment \< 72 hours prior to enrollment.
10. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis. (Brain metastasis - non-progressive or previously treated and currently stable - are permitted.)
11. Active inflammatory neurological disorders (e.g., Guillain-Barre Syndrome, amyotrophic lateral sclerosis, multiple sclerosis).
12. Active autoimmune disease (e.g., lupus, rheumatoid arthritis, Sjogren's syndrome) requiring systemic disease modifying agents in the past 2 years.
13. Active or uncontrolled hepatitis B or C (HCV ribonucleic acid \[RNA\] positive) infection or any history of or active human immunodeficiency virus (HIV) infection.
14. Uncontrolled, acute, or life-threatening bacterial, viral, or fungal infection. Subjects with ongoing use of prophylactic antibiotics, antifungals, or antivirals are eligible if no evidence of active infection.
15. Class III or IV heart failure (as defined by the New York Heart Association - NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease within 6 months prior to Screening.
16. Cardiac arrhythmia not controlled by medical management.
17. Clinically significant thrombotic events within 6 months prior to leukapheresis and/or inability to stop anti-coagulation for at least 2 weeks prior to TAC01-HER2 infusion.
18. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, non-metastatic squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
19. Pregnant or lactating.
20. As determined by the Investigator, any uncontrolled medical, psychological, familial, sociological, or geographical condition(s) that do(es) not permit compliance with the protocol.
21. Participation in or has participated in a study using an investigational device within 4 weeks prior to study treatment..
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the subject's participation for the full duration of the study, such that it is not in the best interest of the subject to participate, in the opinion of the treating investigator.
23. Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study.

    Combination Arm Only Specific Exclusions:
24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
25. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE).
26. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
27. Has received radiation therapy to the lung that is \>30 Gy within 6 months of the first dose of trial treatment.
28. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
29. Has history of an allogeneic stem cell transplant or a solid organ transplant.
30. Has a history of radiation pneumonitis. (Note: Cannot receive prior radiotherapy within 2 weeks of start of pembrolizumab. Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation \[≤2 weeks of radiotherapy\] to non-CNS disease).