Part VIII · Therapeutic foundations · Chapter 48

Immunotherapy

Why the response rates sit where they do, and what the adjuvant-only failure tells us.

1 · Immune checkpoint blockade

A checkpoint inhibitor releases a brake. It does not create a response. The size of the effect is therefore set by what was already happening before the first dose1,2. In breast cancer that starting context is usually unfavourable, and Why response rates in breast cancer sit where they do is where that argument is made in full.

Where the class is established is early triple-negative disease given with chemotherapy. In KEYNOTE-522, pathological complete response was 64.8% with pembrolizumab plus chemotherapy against 51.2% with chemotherapy alone, among the first 602 patients randomised3. Median follow-up later reached 75.1 months. Overall survival at 60 months was 86.6% in 784 patients on pembrolizumab and chemotherapy, with a 95% confidence interval of 84.0 to 88.8. It was 81.7% in 390 patients on chemotherapy alone, with an interval of 77.5 to 85.24.

In metastatic triple-negative disease the effect is concentrated in an assay-defined subgroup. PD-L1 positive is not one measurement. The trials below do not share an antibody, a scored cell population or a cut-point, which is why the assay and threshold are named at each first use here. The full argument is in Predictive biomarkers and patient selection.

KEYNOTE-355 added first-line pembrolizumab to chemotherapy. Among patients with a PD-L1 combined positive score of 10 or more on the 22C3 assay, median overall survival was 23.0 months against 16.1 months. The hazard ratio for death was 0.73, with a 95% confidence interval of 0.55 to 0.95. Among patients with a score of 1 or more the figures were 17.6 and 16.0 months. There the hazard ratio was 0.86, with an interval of 0.72 to 1.04, and it did not meet the significance criterion5. Loosening the threshold diluted the effect to nothing.

Atezolizumab with nab-paclitaxel gave a consistent pattern in the same setting. Median progression-free survival in the intention-to-treat population was 7.2 against 5.5 months, with a hazard ratio of 0.80. In the subgroup called positive by the SP142 immune cell assay, meaning PD-L1-expressing immune cells covering at least 1% of tumour area, it was 7.5 against 5.0 months, with a hazard ratio of 0.62. That is a different antibody and a different scored population from the combined positive score above, and the two subgroups are not interchangeable. Median overall survival in the intention-to-treat population was 21.3 against 17.6 months, with a hazard ratio for death of 0.84 and an interval of 0.69 to 1.026.

2 · Predictive biomarkers and patient selection

Four candidate biomarkers exist and each has a measurement problem that is larger than its biological problem.

PD-L1 is the one in use and it is not one test. The combined positive score, read on the 22C3 antibody, counts PD-L1-staining tumour cells, lymphocytes and macrophages, divides by the number of viable tumour cells and multiplies by 1005. The immune cell score used in the atezolizumab trials is read on the SP142 antibody and records the proportion of tumour area covered by PD-L1-expressing immune cells6,7. Those are different quantities, computed from different denominators with different antibodies. They are not two measurements of one property. A result is interpretable only alongside the assay and cut-point that produced it.

Tumour-infiltrating lymphocytes are prognostic and reproducibly scored under a published convention. They are not established as predictive of checkpoint benefit. The scoring convention and its pitfalls are in8,9. The subtype distribution is in10,11 and the prognostic value in triple-negative disease in12,13. The biology is developed in Tumor-infiltrating lymphocytes, biology and standardized scoring.

Tumour mutational burden and mismatch repair deficiency carry tumour-agnostic evidence14,15, and neither study included a breast cohort. High burden is also uncommon in this disease16, so the eligible population is small before the question of whether the inference transfers is even reached.

Spatial organisation predicts better than any single marker and is not measurable in routine practice. Triple-negative tumours stratify into distinct spatial immune microenvironments17,18, and exclusion driven by TGF-beta signalling in the stroma identifies non-responders in other diseases19.

Caution

PD-L1 positive is the output of a specified antibody, scoring algorithm and cut-point. It is not a property of a tumour. A patient scored positive by one assay and negative by another has not changed, and neither has the tumour. The general form of this problem, where an assay boundary becomes an eligibility boundary, is in Antigen thresholds as eligibility criteria, the general lesson.

3 · Combination with chemotherapy and targeted agents

Checkpoint blockade in this disease is a combination therapy, and there are three mechanistic reasons rather than one.

Cytotoxic therapy supplies antigen and changes the infiltrate. Neoadjuvant chemotherapy alters tumour-infiltrating lymphocyte density and PD-L1 expression in breast cancer tissue20. S-phase-specific DNA damage activates STING-dependent innate immune signalling in breast cancer21, and cytosolic DNA is a general route from genome damage to innate sensing22,23.

The neoadjuvant evidence is consistent across two trials with different agents. In KEYNOTE-522, chemo-immunotherapy raised pathological complete response and later overall survival3,4. With atezolizumab, pathological complete response was documented in 95 of 165 patients, which is 58%, against 69 of 168, which is 41%. The rate difference was 17 percentage points, with a 95% confidence interval of 6 to 27. In the population called positive by the SP142 immune cell assay at the 1% threshold, the figures were 53 of 77 against 37 of 757.

Conjugates are the combination partner with the strongest preclinical rationale and no phase 3 breast cancer result, and that case is made in Combination strategies with immunotherapy and DNA repair agents.

Endocrine therapy is the combination that has not been shown to work. There is a coherent argument that luminal immune quiescence is part of the endocrine-dependent transcriptional program rather than a separate property, which would predict that relieving the dependence changes the immune context Tumor genotype and the immune microenvironment. There is no established clinical evidence that endocrine manipulation improves benefit from checkpoint blockade in this disease.

4 · Vaccines and immune priming

The obstacle is not antigen delivery. It is that there is often no response worth amplifying, and that the antigens available are mostly self.

Breast cancer carries a low mutational burden relative to the histologies where checkpoint blockade works16, so the supply of tumour-specific neoantigens is small. Vaccines against shared overexpressed proteins are therefore targeting self antigens against which central and peripheral tolerance already operate. No breast cancer vaccine has an established place in treatment, and the reason is mechanistic rather than a failure of formulation.

Priming is the more useful framing, and it is what the neoadjuvant setting provides without a vaccine. An intact primary tumour and its draining nodes place antigen and naive T cells in the same anatomical compartment, which is the basis of the systemic immunity and nodal priming argument in Systemic immunity, lymph node priming, and immune memory. The clinical consequence of that is developed in Why response rates in breast cancer sit where they do and it is the strongest available evidence that priming matters.

In situ approaches, meaning intratumoural injection or focal radiation given to convert a lesion into an antigen source, follow the same logic. They have no established result in breast cancer and should be described as a rationale rather than a strategy.

5 · Cellular therapies and immune-engaging antibodies

Adoptive cell transfer has a proof of principle in this disease and it is one patient. A woman with chemorefractory hormone receptor positive metastatic breast cancer received tumour-infiltrating lymphocytes reactive against four mutant proteins, given with interleukin-2 and checkpoint blockade. The targets were mutant SLC3A2, KIAA0368, CADPS2 and CTSB. She had a complete durable regression ongoing beyond 22 months at report24. That establishes that mutation-reactive T cells exist in luminal breast cancer and can be expanded. It does not establish a therapy, and the distance between those two statements is the whole current problem.

Engineered T cells face three obstacles in solid tumours and antigen heterogeneity is the one this book has already characterised. Trafficking into the tumour is the first. The suppressive microenvironment is the second Functional states of the microenvironment. The third is that a receptor-directed effector requires the receptor, which is the same constraint that limits a naked antibody Consequences for response to antibodies and tyrosine kinase inhibitors. The modalities that tolerate heterogeneity are collected in Bystander-capable modalities as a heterogeneity-tolerant strategy.

T cell engaging antibodies redirect a T cell to a surface antigen without requiring that antigen to be a driver. That is attractive for the same reason conjugates are, because it converts a dependency problem into an access problem. There is no established breast cancer result.

Effector-engaging antibodies are already in routine use and are not usually described as immunotherapy. Trastuzumab acts partly through antibody-dependent cellular cytotoxicity25 Innate immunity, natural killer cells, and antibody-dependent cytotoxicity, and blocking the macrophage checkpoint CD47 alongside it eliminated HER2-positive cells and overcame trastuzumab tolerance in preclinical models26.

6 · Immune resistance mechanisms

Primary and acquired resistance are different problems and in breast cancer the first dominates. The reasons are developed in Immunotherapy resistance, primary and acquired and Primary and acquired resistance to checkpoint blockade and the clinical statement is that most tumours in this disease were never going to respond, rather than that they escaped.

Acquired resistance has a defined mechanistic core, and the clearest human evidence is from melanoma. Four patients relapsed after an initial response to pembrolizumab, and paired whole-exome sequencing was performed. Two carried loss-of-function mutations in JAK1 or JAK2 with deletion of the wild-type allele. A third carried a truncating B2M mutation27. The first two lost the ability to respond to interferon gamma. The third lost surface class I major histocompatibility complex. Those are the two axes, and the breast cancer versions are in MHC loss and antigen presentation defects and Primary and acquired resistance to checkpoint blockade.

Exclusion is a third route and it is stromal rather than tumour-intrinsic. TGF-beta signalling in fibroblasts keeps T cells out of the tumour bed and attenuates response to PD-L1 blockade19. A tumour resisting by exclusion has intact antigen presentation and an intact interferon response, so no tumour-cell assay will detect it.

Host factors are a fourth. Interferon signalling diminishes with age and is associated with checkpoint blockade efficacy in triple-negative models28, which makes age a variable in the immune context rather than only in tolerance of treatment.

The measurement limitation should be stated rather than implied. Rebiopsy at progression on immunotherapy is uncommon in breast cancer practice and rarer still in trials, so the acquired resistance literature in this disease is thin. Most of what is written about it is transferred from other tumour types.

7 · Immune-related toxicity and its management

The toxicity is the mechanism, which is why it does not resemble chemotherapy toxicity in timing, in organ distribution or in reversibility. Management is codified in guideline form29 and three structural facts matter more than any individual regimen.

Onset is not dose-related and it is often delayed. Events appear months into treatment and after it has stopped, so a patient who tolerated six cycles is not thereby low risk.

Reversibility differs by organ. Colitis, hepatitis and pneumonitis usually resolve with immunosuppression. Endocrinopathy frequently does not, and hypophysitis or primary thyroid failure leaves lifelong replacement whether or not the drug is stopped.

The same numerical grade carries different urgency in different organs. Grade 2 dermatitis and grade 2 pneumonitis are not comparable clinical events, which is why grade-based algorithms have organ-specific branches29.

The consideration specific to breast cancer is the population. In KEYNOTE-522 more than half the patients in the control arm reached a pathological complete response without pembrolizumab3. Permanent endocrinopathy in a patient who would have been cured without the drug is a different calculation from the same event in metastatic disease, and the conversation held before treatment should reflect that.

Caution

Tumour burden can increase before it falls under checkpoint blockade. That is why the response framework for these agents requires confirmation of progression on a subsequent assessment30. A single scan is not definitive. Stopping an effective drug on one scan is the avoidable error here. Continuing an ineffective one on the same reasoning is the other.

8 · Why response rates in breast cancer sit where they do

This is the chapter's carried argument, and it has three components that are separable and all prior to the drug.

The first is antigen supply. Breast cancer carries a low mutational burden relative to the histologies where single-agent checkpoint blockade works, and high burden is uncommon within it16. The populations defined by mismatch repair deficiency and by high mutational burden respond well and are small15,14.

The second is immune context by subtype, which is the luminal deficit developed in Breast cancer immunology and Functional states of the microenvironment. Tumour-infiltrating lymphocyte density is lowest in hormone receptor positive disease and highest in triple-negative and HER2-positive disease10,11, and the subtype pattern is set out in Immune contexture by subtype and the luminal deficit. There is a further possibility, which is that immune quiescence is part of the oestrogen-driven transcriptional program rather than a property that happens to accompany it Tumor genotype and the immune microenvironment. If that is right, the deficit is a consequence of the dependency being treated, and it is modifiable in principle. It is not established.

The third is timing relative to an intact tumour, and this is where the evidence is sharpest. One trial added atezolizumab to postoperative chemotherapy in stage II or III triple-negative disease, with no neoadjuvant phase. Invasive disease-free survival events occurred in 141 of 1101 patients receiving atezolizumab and chemotherapy, which is 12.8%. They occurred in 125 of 1098 receiving chemotherapy alone, which is 11.4%. The final stratified hazard ratio was 1.11, with a 95% confidence interval of 0.87 to 1.42 and a p value of 0.38. Enrolment was halted at 2199 of a planned 2300 patients after a futility analysis. Grade 3 or 4 treatment-related adverse events occurred in 54% against 44%, and chemotherapy exposure was similar in the two groups31.

Read that against KEYNOTE-522, where the same class given before surgery improved pathological complete response and then overall survival3,4. Same disease, same broad class of agent, benefit when the tumour was in place and none when it was not.

The mechanistic reading is that an intact primary and its draining nodes are the compartment where antigen and naive T cells meet, which is the priming argument in Systemic immunity, lymph node priming, and immune memory. Resection removes the antigen source and disrupts the nodal architecture, so adjuvant checkpoint blockade is asked to amplify a response with nothing left to prime it.

Caution

The two trials differ in more than timing. One used a PD-1 antibody with a platinum-containing regimen and the other a PD-L1 antibody without platinum, and the eligible populations were defined differently. Timing is the most economical explanation for the contrast. It is not the only one, and no trial has isolated it. Presenting the comparison as a controlled test of timing overstates what these two results can carry.

Interplay

The immune argument and the heterogeneity argument are the same argument. Immune pressure selects among a mixed population exactly as drug pressure does, so a tumour with variable antigen presentation loses the presenting compartment first. What makes the immune case distinctive is that the effector recognises a context rather than a receptor. That is why immune mechanisms sit alongside bystander-capable conjugates in Bystander-capable modalities as a heterogeneity-tolerant strategy, as one of the few heterogeneity-tolerant strategies available.

See Integrative biological interplay

References

All 31 references
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