Cancer Immunotherapy and Immune Trade-offs

Course Information and Introductory Overview

Course Details:

• Date: May 4, 2026

• Course Number: $BIOL424$ Spring 2026 (Class 15a)

• Instructor: Catherine Brennan

• Topic: Cancer Immunotherapy, focusing specifically on the mechanisms and roles of macrophages and Cytotoxic T Lymphocytes ($CTLs$) in combating malignancy.

Core Themes & Questions:

• What mechanisms allow cancer to persist despite the immune system's inherent ability to target and eliminate tumors?

• A thorough examination of groundbreaking cancer immunotherapy treatments and their clinical trials.

• An in-depth discussion on specific therapies, including the $ext{α-CD47}$ checkpoint blockade and innovative cancer antigen vaccination strategies combined with checkpoint blockade, particularly in melanoma cases.

Administrative Updates:

• In light of student performance, the lowest midterm grade has been eliminated from final calculations for all students.

• Evaluation response rates as of May 8, 2026: 100 ext{%} for Section 01 and 93 ext{%} for Section 03.

The Immunological Trade-off: Autoimmunity vs. Cancer

The immune system operates on a precarious balance, existing in a constant state of tension between under-reacting and over-reacting.

1. Under-reacting:

   • A lack of adequate immune response can result in heightened susceptibility to infections and malignancies since the body fails to identify and eradicate aberrant cells or invasive pathogens.

2. Over-reacting:

   • An aggressive immune response can precipitate autoimmunity, where the immune system erroneously targets and attacks the body’s own healthy tissues.

Illustrative Example: Tyrosinase and Vitiligo

• Vitiligo:

  • An autoimmune disorder characterized by the destruction of melanin-producing cells, primarily mediated by $CTL$ targeting of tyrosinase, a crucial enzyme involved in the synthesis of melanin.

• Allelic Variation at Position $402$:

  • Two alleles of tyrosinase exist at this genetic locus: Arginine (R) and Glutamine (Q).

    • $ext{Arg}(R402)$ (The "older" allele):

      • This allele is associated with a greater susceptibility to vitiligo but exhibits resistance to melanoma. It is effectively presented by $HLA-A*0201$ ($Class ext{ I MHC}$).

    • $ext{Gln}(Q402)$ (The "newer" allele, prevalent in individuals of European descent):

      • This allele offers resistance to vitiligo yet increases susceptibility to skin cancers, such as melanoma, due to its ineffective presentation of the peptide ($QMDGTMSQV$) via $HLA-A*0201$.

• The Trade-off:

  • Individuals carrying $HLA-A*0201$ with the $Tyr402R$ allele may be susceptible to vitiligo (an autoimmune response) while simultaneously benefiting from protection against melanoma (a malignancy). This scenario demonstrates how robust immune reactions to self-antigens that mark cancer cells can safeguard against cancer at the potential cost of inducing autoimmune disorders.

Systemic Lupus Erythematosus (SLE) and Apoptosis Defects

Systemic Lupus Erythematosus (SLE) is recognized as a complex autoimmune disease marked by the generation of autoantibodies targeting various "nuclear antigens," including histones, double-stranded DNA ($dsDNA$), and small nuclear ribonucleoproteins ($snRNPs$).

Symptoms & Pathology:

• Symptoms of SLE may include:

  • Rash

  • Fever

  • Profound weakness

  • Dysfunctional kidney operations

• The disease is triggered by fundamental defects in two core biological processes:

  1. Apoptosis:

     • The programmed death of cells.

  2. Phagocytosis of apoptotic cells:

     • The essential process of clearing cellular debris following cell death.

Mechanism of Autoimmunity in Lupus:

• Normal Apoptosis:

  • In a healthy scenario, cells undergo death and fragment into membrane 'blebs' that macrophages subsequently remove without inciting inflammation.

• Impaired Apoptosis/Phagocytosis:

  • When clearance mechanisms become compromised, dying cells can release self-molecules, including DNA fragments.

• TLR Activation:

  • Dendritic Cells ($DCs$) possess receptors that recognize DNA and RNA, particularly through $TLR7$ and $TLR9$. In the absence of infectious agents, $DCs$ can be erroneously activated by binding self-DNA via $TLR9$.

• Lymphocyte Priming:

  • Once activated, these $DCs$ express $CD80/86$ costimulatory molecules and migrate to lymph nodes, priming naive $T$ cells to react against self-proteins (like anti-histone).

  • Naive $B$ cells equipped with receptors ($BCR$) that bind to DNA or histones can be activated, culminating in the hallmark anti-nuclear antibodies ($ANAs$) characteristic of lupus.

Multiple Sclerosis (MS) and Molecular Mimicry

Multiple Sclerosis (MS) is known to be an autoimmune disorder wherein antibody-mediated actions cause damage to the myelin sheath that insulates neuronal axons.

The Viral Trigger:

• MS predominantly manifests in individuals with a history of infection with Epstein-Barr Virus (EBV) (which is present in an estimated 95 ext{%} of the population).

• Mechanism: Molecular Mimicry:

  • EBV expresses a protein identified as $EBNA$ (EB-nuclear-antigen). This protein contains a sequence that closely resembles $GCAM$ (glial cell adhesion molecule), which is a human protein localizing on glial cells.

• The Failure of Central Tolerance:

  • Typically, self-reactive lymphocytes are eliminated through a mechanism known as negative selection. However, this could fail against phosphorylated forms of self-antigens, allowing self-reactive lymphocytes to persist in the peripheral circulation.

• Pathological Outcome:

  • The immune response sparked by $EBV$ may inadvertently cross-react with $GCAM$, culminating in the destruction of myelin sheaths surrounding neurons.

Spontaneous Remission: The SARS-CoV-2 Case Study

A notable clinical case reported between 2020 and 2021 involved a $61$-year-old man suffering from end-stage renal failure and $EBV$-positive classical Hodgkin lymphoma.

• Initial State:

  • The patient presented with progressive lymphadenopathy and significant weight loss; $EBV ext{-PCR}$ levels were recorded at $4800 ext{ copies/ml}$ ($log_{10} ext{-}3.68$).

• Event:

  • Following contraction of $SARS-CoV-2$ pneumonia, he received solely supportive care without the administration of corticosteroids or chemotherapy.

• Outcome:

  • Four months post-infection, there was a remarkable resolution of lymphadenopathy, with PET scans reflecting a considerable reduction in metabolic uptake. The $EBV ext{-PCR}$ levels lowered to $413 ext{ copies/ml}$.

• Hypothesis:

  • The viral infection likely triggered a robust anti-tumor immune response, with potential mechanistic pathways including:

  1. Cross-reactivity:

     • Pathogen-specific $T$ cells targeting tumor antigens.

  2. NK Cell Activation:

     • The inflammatory cytokines generated during the viral response could activate Natural Killer ($NK$) cells responsible for attacking the lymphoma.

History of Immunotherapy: William Coley

William Coley (1890s):
A pioneering bone surgeon often referred to as the "Father of Immunotherapy."

• Observation:

  • After losing a patient to bone cancer, Coley found historical accounts detailing the regression of sarcoma post-infection with $Streptococcus pyogenes$ (which caused erysipelas).

• Experimentation:

  • He began injecting live bacteria into tumors, achieving regression in some cases, but often resulting in severe septic shock or life-threatening infections.

• "Coley’s Toxins":

  • Coley later transitioned to using dead bacteria for injections. His revised treatment garnered numerous documented accounts of "astounding cures."

• Mechanism:

  • Coley’s Toxins primarily acted by overcoming peripheral tolerance. By eliciting a substantial inflammatory environment, he created conditions of "DC confusion," where Dendritic Cells matured due to $TLRs$ activating in response to microbial ligands, leading to self-tumor peptides being presented in the presence of costimulatory signals ($CD80$).

• Transition of Care:

  • Following the advent of X-rays ($1895$) and subsequent developments in radiation and chemotherapy (influenced by World War II chemical warfare research), immunotherapy saw a decline in popularity.

Macrophage-Mediated Cancer Fighting

Macrophages showcase a considerable capacity to combat cancer, yet their efficacy is frequently hampered by cellular signaling interactions.

• The "Don't Eat Me" Signal ($CD47$):

  • Normal, healthy cells express $CD47$; through binding to the $ext{SIRP-} ext{α}$ receptor on macrophages, this binding inhibits phagocytosis.

• Cancer Evasion:

  • Cancer cells often increase $CD47$ expression to evade recognition and destruction by macrophages.

• Therapy:

  • Inhibiting the interaction between $CD47$ and $SIRP-α$ empowers macrophages to identify and eradicate cancer cells effectively. Moreover, fostering this phagocytic uptake can enhance antigen presentation to $T$ cells via $DCs$.

Cytotoxic T Lymphocytes (CTLs) and Checkpoints

$CTL$ Function:

• $CTLs$ contribute to the elimination of cancer cells by inducing apoptosis. This role is underscored by evidence indicating that immunocompromised individuals (such as those with HIV and the so-called "bubble boy" cases) as well as $RAG$-mutant or perforin-mutant mouse models show heightened tumor vulnerability.

• Recognizing Cancer:

  • $CTLs$ discern tumor cells by recognizing "cancer antigens" presented on $Class ext{ I MHC}$ molecules. These antigens generally arise from protein mutations or altered expression levels.

• Checkpoint Blockade Therapies:

  • Tumors commonly exploit inhibitory receptors that are normally involved in preventing autoimmunity to escape immune destruction.

  • $CTLA-4$:

    • An inhibitory receptor that hinders early $T$ cell activation.

  • $PD-1/PD-L1$:

    • A checkpoint pathway suppressing $T$ cell activity in tissue environments. Many tumors express $PD-L1$ to deactivate attacking $T$ cells.

Major Checkpoint Inhibitors:

• Ipilimumab (Yervoy):

  • Targets $CTLA-4$.

• Pembrolizumab (Keytruda):

  • Targets $PD-1$ (notably used successfully by Jimmy Carter for brain-metastatic melanoma).

• Nivolumab (Opdivo):

  • Targets $PD-1$.

• Durvalumab (Imfinzi):

  • Targets $PD-L1$.

Personalized Medicine: Neoantigens and Vaccines

Mutational Load:

• There exists a direct correlation between the number of exomic missense mutations within a tumor and the efficacy of checkpoint blockade strategies, such as Yervoy.

• Criteria:

  • Patients classified with >100 mutations (high mutational load) typically demonstrate superior long-term benefits due to the higher likelihood that "neoantigens" (novel, mutated peptides) emerge that the immune system can recognize as foreign entities.

Personalized Neoantigen Vaccination (Ott et al., 2017):

1. Sequencing:

   • Conduct a thorough DNA and RNA sequencing of the patient's tumor to identify unique mutations.

2. Target Selection:

   • Utilize computational prediction methods to ascertain which mutated peptides will effectively bind to the individual's specific $HLA$ ($MHC$) alleles.

3. Vaccine Manufacture:

   • Synthesize long peptides based on identified neoantigens for the vaccine composition.

4. Adjuvant:

   • The vaccine should be co-administered with poly ICLC (an adjuvant that simulates viral RNA to stimulate $DCs$).

5. Result:

   • This comprehensive approach "unleashes" $CTLs$ against the tumor, and when combined with $anti-PD-1$ therapy, it can yield synergistic effects.

Summary: Strategies to Break Tolerance

Cancer immunotherapy is centered on the principle of breaking tolerance—crippling tumor cells through controlled autoimmunity, involving:

• $Anti-CD47$ therapy:

  • Augmenting macrophage-mediated phagocytosis.

• Checkpoint Blockade ($PD-1, CTLA-4$):

  • Exerting removal of inhibitory signals from the immune response.

• Personalized Vaccination:

  • Educating $T$ cells to identify and attack tumor-specific neoantigens.

• Adjuvants:

  • Implementing inflammatory cues to ensure adequate maturation and costimulation of $DCs$ ($$CD