Overview

• Grade Level: AP Biology / AP US History / AP World History / General Health Science (grades 9-12)

• Time Required: Single class (45 minutes); bell-ringer option (10 minutes); extension (2 additional class periods)

• Historical Period: Late-nineteenth-century American medicine, 1890 to 1936

• Modern Connection: The May 2026 reporting at the American Association for Cancer Research annual meeting of the NEOPRISM-CRC trial, in which thirty-two patients with stage two and three mismatch-repair-deficient bowel cancer were given pre-surgical immunotherapy and have remained relapse-free at thirty-three months of follow-up

Learning Objectives

Students will be able to:

1. Describe the immune system's general response to bacterial infection, including the role of fever, cytokines, and the activation of innate and adaptive immunity.

1. Explain the historical observation, made by William Coley in the 1890s, that severe bacterial infection sometimes correlated with the regression of cancer, and analyse the methodological strengths and weaknesses of his clinical evidence.

1. Compare the principle behind Coley's Toxins (whole-bacterial activation of the immune system) with the principle behind modern checkpoint-inhibitor immunotherapy (selective release of immune brakes), and identify the underlying continuity.

1. Construct an argument, using both the historical and modern evidence, about why an idea can be both correct and rejected by the medical establishment of its time.

Before Reading

Anticipation Questions

1. If a patient with terminal cancer accidentally caught a serious bacterial infection in the hospital and the cancer then disappeared, what would the doctors in 1891 have concluded? What would the doctors in 2026 conclude? Why might those answers differ?

1. Imagine a treatment for a fatal disease that works in about half of patients but cannot be standardised, has violent side effects, and depends on the immune response of each individual. Should the medical establishment of any era endorse it? Defend your answer.

1. What do you understand by the word cure in medicine? When are doctors allowed to use it?

Key Vocabulary

• Sarcoma: A cancer of connective tissues, including bone, cartilage, fat, muscle, blood vessels and nerves. Distinct from the more common carcinomas, which arise from epithelial tissues.

• Erysipelas: A bacterial skin infection, classically caused by Streptococcus pyogenes, characterised by a sharply demarcated bright-red rash, fever, and swelling.

• Streptococcus pyogenes / Serratia marcescens: The two species of heat-killed bacteria that William Coley combined in his "mixed bacterial vaccine," known as Coley's Toxins.

• Immunotherapy: Cancer treatment that activates or augments the patient's own immune system to attack tumour cells, in contrast to surgery (removal), radiation (destruction), or chemotherapy (chemical kill).

• Pembrolizumab: A monoclonal antibody that blocks the PD-1 receptor on T cells. By blocking PD-1 it removes a brake the tumour was using to evade immune attack. Trade name Keytruda. Approved for an expanding list of cancers since 2014.

• Mismatch-repair-deficient (dMMR) / MSI-high (microsatellite instability high): A genetic profile in which the cancer's DNA-repair machinery is broken, leading to a high mutational load. These cancers tend to respond strongly to checkpoint immunotherapy because their many mutations make them visible to the immune system.

• Checkpoint inhibitor: A class of drug, including pembrolizumab (PD-1) and ipilimumab (CTLA-4), that removes molecular brakes the immune system normally uses to prevent self-attack. By removing those brakes in the right patients, the drug allows the immune system to attack tumours.

• NEOPRISM-CRC: The Phase II UK trial reporting at AACR 2026, in which 32 patients with stage 2 or 3 dMMR/MSI-high colorectal cancer received three cycles of pembrolizumab before surgery; all were relapse-free at a mean of 33 months.

During Reading

Guided Questions

1. Note the precise date and place of Coley's first deliberate infection of a cancer patient. Note also what made him willing to try it.

1. Identify three reasons the medical establishment of the early twentieth century rejected Coley's Toxins.

1. What specifically did Helen Coley Nauts do, between 1936 and 1953, to keep her father's work available to later researchers?

1. List three concrete numbers from the NEOPRISM-CRC trial that make the May 2026 result remarkable.

After Reading

Discussion Questions

1. The story argues that the medical establishment of the 1920s was "right to reject" Coley in some sense and "wrong to reject" him in another sense. What is the distinction the story is drawing? Do you accept it?

1. Helen Coley Nauts had no medical training. She still managed to keep her father's evidence in scientific circulation for half a century. What does that say about who gets to be a scientist?

1. The NEOPRISM-CRC trial enrolled only 32 patients. How confident should we be in its conclusions? What further trials would you want to see before changing standard practice?

1. The story describes the dMMR/MSI-high genetic profile as a "subgroup" of colorectal cancer that responds especially well to immunotherapy. Should treatments be approved separately for genetic subgroups rather than for tumour locations (lung, breast, colorectal)? What changes if they are?

1. (Genuinely debatable.) The story ends by saying "we are now allowed to say" the fever was the cure all along. Does that mean Coley was right? Does it mean the establishment was wrong? Or is the real question more complicated?

The Parallel

1. List the structural features that are similar between Coley's 1891 approach and modern checkpoint immunotherapy. List the features that are different. Which list is longer, and which is more important?

1. The story claims a continuous lineage from Coley's Toxins (1891) to the 2018 Nobel Prize to NEOPRISM-CRC (2026). Is "lineage" the right word, or is it too neat?

1. What do you think Coley would have done differently if he had been working today? What would he have been unable to do that he tried in 1891?

Activities

Bell-Ringer (10 minutes)

Display two photographs side by side: a Victorian-era hospital ward (Bellevue or Memorial in the 1890s) and a modern AACR oncology conference auditorium. Ask students: "What two things in these images are doing the same job?" Have them write two sentences identifying a continuity and a difference. Use the responses to introduce the story.

Single Class (45 minutes)

• 0 to 5 minutes: Bell-ringer recap. Display the two photographs.

• 5 to 18 minutes: Read the historical half of the story aloud or play the audio narration. Students fill out a guided-reading organiser with three columns: "What Coley observed," "What Coley proposed," "Why the establishment rejected him."

• 18 to 30 minutes: Read the modern half aloud or play the audio. Students extend the organiser with parallel columns: "What NEOPRISM-CRC observed," "What the trial proposed," "How the field is responding."

• 30 to 42 minutes: Structured small-group discussion of After Reading question 5 (was Coley right?). Each group constructs one one-paragraph argument and one one-paragraph counter-argument.

• 42 to 45 minutes: Exit ticket. One sentence: "The most important thing Coley's story can teach the 2026 immunotherapy era is: ___."

Extension Activity

Source-comparison essay (3 to 5 pages, two class periods): students locate one of William Coley's original papers (1893 or later, available at the Yale Manuscripts and Archives collection or through PubMed Central reprints), one modern review of checkpoint immunotherapy, and one news article about NEOPRISM-CRC. They write a short essay comparing the kinds of evidence each source presents, the kinds of arguments it makes, and the kinds of audience it addresses, and propose one additional claim each source could responsibly have made (or one claim each should have hedged more).

Primary Source Connections

• William B. Coley, "The Treatment of Malignant Tumors by Repeated Inoculations of Erysipelas: With a Report of Ten Original Cases," American Journal of the Medical Sciences (1893). Coley's first major published paper. Type: original clinical paper. Available through PubMed Central and the Yale Manuscripts and Archives collection.

• Helen Coley Nauts, "End Results in 449 Cases of Bone Sarcoma," Cancer Research Institute Monograph series (1953 onwards). Nauts's compiled and re-graded patient records. Type: statistical compendium. Available through the Cancer Research Institute and Yale Archives.

• The Helen Coley Nauts Papers, MS 0010, Manuscripts and Archives Collection, Sterling Memorial Library, Yale University. Type: archival collection (15,000 letters and patient files). Access by appointment.

• James P. Allison, "Immune Checkpoint Blockade in Cancer Therapy," Nobel Lecture, 7 December 2018, Aula Medica, Karolinska Institutet. Type: Nobel lecture. Available at nobelprize.org with full transcript and video.

• NEOPRISM-CRC Trial, registered protocol, ClinicalTrials.gov (UCL/UCLH). Type: clinical trial protocol. The 2026 follow-up data was presented by Yanrong Jiang at AACR 2026, abstract available through aacrjournals.org.

Standards Alignment

C3 Framework

• Dimension 1 (Developing Questions): Compelling question: "How does a correct idea survive an unwelcome reception, and how does it eventually return?" Supporting questions about the role of evidence, the role of institutions, and the role of family archives in the history of science.

• Dimension 2 (Applying Concepts): Biology (innate and adaptive immunity, the role of fever, T cells, mutational burden). History (the institutionalisation of medicine in the late nineteenth century). Civics (the role of the American Cancer Society, the FDA, and the AACR in defining medical orthodoxy). Geography (the global cohort structure of modern oncology trials).

• Dimension 3 (Evaluating Sources): The story is accompanied by a populated evidence manifest with seventeen verified claims and direct source URLs. Students can interrogate each claim by clicking through.

• Dimension 4 (Communicating Conclusions): The structured debate activity (Single Class, 30 to 42 minutes) and the extension essay both require sustained argumentation.

AP Alignment

• AP Biology: Big Idea 3 (Living systems store, retrieve, transmit, and respond to information essential to life processes) and Big Idea 4 (Biological systems interact, and these systems and their interactions possess complex properties). Cellular signalling, the immune response, and tumour-immune system interaction.

• AP US History: Period 7 (1890 to 1945) and Period 8 (1945 to 1980). The rise of the modern American hospital, the founding of the National Cancer Institute (1937), and the institutionalisation of biomedical research.

• AP World History: Key Concept 6.3 (New Conceptualizations of Global Economy, Society, and Culture). The international structure of twenty-first-century clinical trials.