Chapter 26 — Exercises

How to use these. No answers are given. Several exercises have more than one defensible answer; what is being trained is the reasoning, not the retrieval. Items marked † are harder — they ask you to go outside the chapter, hold two things at once, or defend a position you may not like.

A standing rule for this chapter. Nothing here is medical advice, and nothing here should be used to decide anything about anyone's cancer care. If an exercise makes you want to look up a trial, that is good. If it makes you want to recommend a trial to someone, stop and reread §26.7.

Set A — The mechanism

A1. In one sentence each, define antigen, epitope, and immunogen, and state what distinguishes each from the other two.

A2. Explain why the sentence "the immune system recognizes the virus" is, at the level of T-cell biology, false — and what the accurate replacement sentence is.

A3. A class I epitope is typically 8–10 residues; a class II epitope is typically 13–25. Explain what structural feature of the two grooves accounts for that difference, and what it implies about which peptides each can display.

A4. Draw (in text) the path a protein made inside a cell takes to become a displayed class I epitope. Label at least four steps.

A5. Using Chapter 1's material on side chains, explain what an anchor residue is and why two peptides with identical middles but different anchors may behave completely differently.

A6. Antibodies mostly recognize conformational epitopes; T cells recognize linear ones. State the practical consequence of that fact for anyone designing a short-peptide vaccine.

A7. Explain, without using the word "memory," what a vaccine actually changes about a person.

A8. † The chapter claims that every T-cell-directed vaccine — live, attenuated, subunit, mRNA — is ultimately a peptide-delivery system. Construct the strongest objection to that claim you can, then say whether you think it survives.

Set B — HLA and the personalization problem

B1. In your own words, define HLA restriction and give a concrete illustration of it.

B2. A peptide vaccine produces a strong T-cell response in one trial participant and no detectable response at all in another. List three distinct explanations consistent with this chapter, and say what data would distinguish them.

B3. A trial protocol states that patients must be positive for a specified class I allele to enroll. Explain what that requirement does to (a) the trial's internal validity and (b) its external validity.

B4. † The chapter argues that HLA-restricted enrollment created an equity problem. Write the strongest defense of the researchers who made that choice at the time, then say what you would ask them to do differently now.

B5. Why does a whole-protein or whole-organism vaccine largely sidestep the HLA restriction problem that a short-peptide vaccine cannot?

B6. A computational tool predicts that 200 peptides from a tumor will bind a patient's HLA. Explain why the number of peptides that will actually produce a T-cell response is substantially smaller, and name at least three of the filters that stand between prediction and response.

B7. † Tumors escape immune attack by losing one parental HLA haplotype. Explain why this is a particularly awkward escape mechanism for a vaccine strategy specifically — more awkward than, say, losing expression of a single target protein.

Set C — Adjuvants and the danger signal

C1. State, in one sentence, why a short synthetic peptide injected in saline is usually a poor immunogen. Give the three separate reasons the chapter lists.

C2. Explain the difference between what happens to a T cell that meets its peptide with costimulation and one that meets it without.

C3. "Vaccination can make the problem worse" is an uncomfortable sentence. Explain the mechanism by which it can be true.

C4. Aluminum salts are excellent for antibody-directed prophylactic vaccines and historically poor for cancer vaccines. Explain why, in terms of the kind of response each application needs.

C5. † The chapter describes a preclinical finding that a persistent injection-site depot can retain and delete the T cells it induced. Explain why this is a preclinical finding rather than a clinical one, what it would take to establish it in humans, and how much weight you think it should carry in designing a trial today.

C6. A patient reports a sore arm and a day of fatigue after a vaccination. Write two sentences explaining what that most likely represents — one for a colleague, one for a worried friend.

C7. Why is the safety bar for a prophylactic vaccine so much higher than for a therapeutic cancer vaccine? Frame your answer in terms of who is being asked to accept the risk and what they get for it.

Set D — Neoantigens and individualized vaccines

D1. Define neoantigen and explain what makes it immunologically different from a tumor-associated antigen. Your answer must use the word tolerance.

D2. Write out the individualized neoantigen vaccine pipeline in your own words, in eight steps or fewer, and mark the step you think is most likely to fail.

D3. Why does the pipeline require sequencing normal tissue as well as tumor tissue? What would go wrong without it?

D4. Explain why synthetic long peptides largely replaced minimal epitope peptides in this field. Your answer should connect to Set C.

D5. Distinguish clonal from subclonal mutations and explain why the distinction matters for target selection.

D6. † Shared "off-the-shelf" neoantigen vaccines target recurrent hotspot mutations. List the advantages of that approach over full individualization, then list what is given up. Say which you would fund first and why.

D7. The chapter says checkpoint inhibitor response is associated with high tumor mutational burden, and treats that as indirect evidence for the neoantigen idea. Explain the inference — and then state precisely what the association does not establish.

D8. † Tumors with few mutations offer little raw material for this approach. Is that a temporary engineering problem or a structural limit? Defend your answer.

Set E — Evidence, ratings, and reading the literature

E1. Reproduce the four-line 📊 Evidence Rating format from memory and explain what job each line does.

E2. The chapter rates peptide-epitope presentation ✅ and individualized neoantigen vaccines 🔬. Explain why no part of the first rating can be used to support the second.

E3. Peptide allergy immunotherapy is ⚠️; neoantigen cancer vaccines are 🔬. Both are unresolved. Explain the distinction using the definitions of the two symbols.

E4. † Write an 📊 Evidence Rating block, in the chapter's exact four-line format, for the claim: "Prophylactic vaccination against human papillomavirus reduces the incidence of cervical cancer." Choose the rating and justify it. Then explain why that claim's rating and this chapter's cancer vaccine rating can differ so sharply while both concern "cancer vaccines."

E5. A single-arm study of 15 patients reports that 11 developed neoantigen-specific T cells and 9 remained recurrence-free at one year. Write the three-sentence critique this chapter would give.

E6. † A press release describes a randomized trial in which the vaccine arm did better on recurrence-free survival. List every question you would need answered before revising a rating, and then rank them by how much each answer would move you.

E7. Explain the attribution problem created by combining a cancer vaccine with a checkpoint inhibitor, and describe the trial design that solves it in principle.

E8. † The chapter says the intervention is "a process, not a molecule," and treats that as a reason for caution. Argue the opposite case: that an individualized platform could be more generalizable than a fixed drug, not less. Then say which argument you find stronger.

Set F — Communication and the dossier

F1. Fill in the immune variant of Field 3 for a hypothetical individualized neoantigen vaccine, from the chapter's template, without looking at the worked demonstration.

F2. Explain to a non-scientist, in four sentences, why "the vaccine leaves your body in a few days" is both true and irrelevant.

F3. † A friend forwards you a headline reading "Personalized cancer vaccine wipes out tumors in trial." Write the reply you would actually send — accurate, not condescending, and no longer than 150 words. Assume your friend has a family member currently in treatment.

F4. Write two sentences a clinician could say to a patient who asks whether they should "get the cancer vaccine." Neither sentence may overstate or dismiss.

F5. † The chapter insists that the immune readout line and the clinical endpoint line in your dossier stay separate. Find one report — news article, press release, or abstract — where those two have been merged, and rewrite its summary sentence with them separated.

F6. In one paragraph, explain why the most successful "cancer vaccines" in existence are prophylactic antiviral vaccines, and why that fact is easy to forget.