Inclusion Criteria:
* Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of botensilimab (AGEN1181) in combination with balstilimab (AGEN2034) in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 (or Karnofsky ≥ 60%)
* Absolute neutrophil count ≥ 1,000/mcL
* Platelets ≥ 100,000/mcL
* Total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN)
* Patients with documented Gilbert's syndrome may be included if total bilirubin is ≤ 3 x ULN
* Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN
* Creatinine clearance ≥ 40 mL/min
* Creatinine clearance (Clcr) can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation
* Histological confirmation of colorectal cancer (adenocarcinoma) (CRC)
* Post-R0 resection of stages II and III CRC and all planned adjuvant therapies have been completed
* No evidence of radiographic disease within 28 days (before or after) of a positive ctDNA assay
* Evident MRD as defined by positive ctDNA (Signatera MRD) assay. MRD status will be confirmed with the Signatera™ assay prior to initiation of therapy. The MRD status should be assessed at least 4 weeks post-surgery and at least 3 weeks after last chemo to avoid transient false positives. The window from MRD positivity to first dose should be no more than 90 days
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
* The effects of botensilimab (AGEN1181) and balstilimab (AGEN2034) on the developing human fetus are unknown. Women of child-bearing potential \[refer to MD Anderson (MDA) Policy CLN 1114\] must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 4 months after the last dose. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:
* Postmenopausal (no menses in greater than or equal to 12 consecutive months)
* History of hysterectomy or bilateral salpingo-oophorectomy
* Ovarian failure (follicle stimulating hormone and estradiol in menopausal range, who have received whole pelvic radiation therapy)
* History of bilateral tubal ligation or another surgical sterilization procedure.)
* Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide. Not engaging in sexual activity for the total duration of the trial and the drug washout period is an acceptable practice; however periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of administration. In addition, women of childbearing age should not donate egg(s) and men should not donate sperm for the duration of study participation and 6 months after completion of the last dose of botensilimab (AGEN1181) and balstilimab (AGEN2034).
* Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
Exclusion Criteria:
* Patients who are receiving any other investigational agents
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to botensilimab (AGEN1181) and balstilimab (AGEN2034)
* Patients that are pregnant, breast feeding, or planning to become pregnant while enrolled in the study, up to the end of treatment (EOT) visit, are excluded from this study because botensilimab (AGEN1181) and balstilimab (AGEN2034) are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with botensilimab (AGEN1181) and balstilimab (AGEN2034), breastfeeding should be discontinued if the mother is treated with botensilimab (AGEN1181) and balstilimab (AGEN2034)
* Patients with microsatellite instability (MSI-high) or deficient mismatch repair (dMMR) CRC (MMR/MSI testing is required prior to enrollment)
* Concurrent treatment with a drug with which the interactions are considered clinically significant by the investigator. Major surgical procedure or significant traumatic injury within 21 days before start of study medication \* Note: If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
* Systemic therapy with immunosuppressive agents within 7 days or use of any investigational drug within 28 days before the start of trial treatment
* Prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy for metastatic (m)CRC
* Receipt of any organ transplantation, including allogeneic stem cell transplantation (exception: transplants that do not require immunosuppression, such as hair transplant)
* Patients with active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
* Patients with known severe hypersensitivity reactions to monoclonal antibodies (grade ≥ 3 National Cancer Institute \[NCI\]-Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 5.0), any history of anaphylaxis, or recent (within 5 months) history of uncontrolled asthma
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
* Patients with clinically relevant diseases (for example, inflammatory bowel disease) and / or uncontrolled medical conditions, which, in the opinion of the Investigator, might impair the subject's tolerance or ability to participate in the trial. Stable, well-controlled conditions such as vitiligo, type 1 diabetes, or hypothyroidism on replacement can be allowed
* Failure to recover from any other toxicity (other than immune-related toxicity) related to previous anticancer treatment to ≤ grade 2
* Receipt of a live-virus vaccine within 30 days prior to first dose of study drug (seasonal flu vaccines that do not contain live virus are permitted)
* Evidence of any serious bacterial, viral, parasitic, or systemic fungal infections within the 30 days prior to the first dose of study drug
* Patients with a history of (non-infectious) pneumonitis that required steroids, ongoing pneumonitis, or history of interstitial lung disease
* Patients with grade \> 3 proteinuria (\> 3.5 g/24 hours)
* Patients with grade \> 3 hypertension (systolic blood pressure \> 160 or diastolic blood pressure \> 100)
* Active autoimmune disease requiring systemic treatment in the past 2 years (e.g., steroids \> 10 mg prednisone equivalent, biologics, other immunosuppressants)
* Active or prior inflammatory bowel disease (Crohn's, ulcerative colitis, microscopic colitis). This is especially critical in colon cancer patients where you might otherwise capture inflammatory bowel disease (IBD)-associated CRC
