This is a small Phase II study testing whether targeted internal radiation treatment (HDREBT) followed by two doses of the immunotherapy drug Nivolumab is safe, practical, and potentially effective before patients undergo surgery (TME) to remove rectal cancer.

Inclusion Criteria:

1. Age ≥18 years at the time of consent.

2. Histologically confirmed rectal adenocarcinoma arising within 5 to 15 cm of the anal verge as measured by sigmoidoscopy or MRI.

3. Rectal cancer staging:

   1. Clinical Stage cT2 or cT3 based on high resolution pelvic MRI;
   2. No evidence of distant metastases (cM0) on contrast -enhanced CT of chest, abdomen and pelvis (or PET/CT if clinically indicated);
   3. Disease deemed technically resectable with curative intent by multidisciplinary tumor board (MDT)*. No radiologic evidence of unresectable local disease (e.g., tumor fixation or invasion of adjacent unresectable structures).

4. At least one of the following adverse prognostic features observed on baseline MRI:

   1. Node-positive disease (cN+);
   2. Threatened mesorectal fascia (MRF) defined as distance from tumor to mesorectal fascia < 1mm on pelvic MRI;
   3. Extramural venous invasion (EMVI+).

5. Proficient mismatch repair (pMMR) status, as determined by immunohistochemistry and/or microsatellite instability-low (MSI-L) status by next-generation sequencing

6. Planned management includes neoadjuvant therapy with radiotherapy followed by curative-intent TME.

7. Prior external beam pelvic radiation for other malignancy (prostate, gynecology, lymphoma, bladder) are acceptable, provided the colorectal surgeon deems the patient as a candidate for TME surgery.

8. ECOG performance status of 0-2

9. Adequate organ function, defined by:

   1. Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
   2. Platelets ≥ 100 x 109/L
   3. Hemoglobin ≥ 90 g/L
   4. Estimated creatinine clearance ≥ 30 mL/min
   5. Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's syndrome who may only be included with total bilirubin ≤ 3.0 x ULN)
   6. Aspartate transaminase (AST) ≤ 3.0 x ULN
   7. Alanine transaminase (ALT) ≤ 3.0 x ULN
   8. INR ≤ 1.5 ULN
   9. aPTT and PT ≤ 1.5 ULN
   10. Albumin ≥ 25 g/L

10. Ability to understand, willing to provide written informed consent, and to comply with study requirements.

Exclusion Criteria:

1. Prior anticancer therapy for rectal cancer.

2. Contraindication to safe MRI imaging.

3. Evidence of bowel obstruction on MRI or clinical evaluation.

4. Evidence of distant metastasis.

5. Medical or surgical contraindications to major pelvic surgery

6. Active autoimmune disease requiring systemic immunosuppressive therapy.

7. Active/uncontrolled infection. Infectious screening for HIV, Hepatitis B (HBV), Hepatitis C (HBC) and tuberculosis will be performed at screening:

   1. Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks; and have undetectable HBV viral load prior to starting treatment. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
   2. Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to start of treatment.
   3. HIV-infected participants must have well-controlled HIV on antiretroviral treatment (ART), defined as:

   i. have a CD4+ T-cell count ≥ 0.35 x109 cells/L at the time of screening. ii. must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.

   iii. must not have had any AIDS-defining opportunistic infections within the past 12 months.

   iv. must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before start of treatment and agree to continue ART throughout the study.

8. Known allergy or hypersensitivity to nivolumab or any of its excipients.

9. Patients with other psychiatric, social or severe or uncontrolled medical conditions that in the opinion of the investigator may compromise their compliance with the protocol or may represent an unacceptable risk to their safety (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled clinically significant cardiovascular disease).

10. Requirement for prohibited concomitant medication, as outlined in section 8.4 within 14 days prior to first brachytherapy treatment.

11. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 28 days of first neo-adjuvant treatment.

12. Patients who are pregnant or breastfeeding or WOCBP not employing an effective method of birth control.