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Humanisation .
Immunotherapeutics in clinical practice .
Presented by Aquib Naseer
M Pharm Pharmacology
School of Pharmaceutical Edu & Research, Jamia Hamdard
Contents :
Humanization :
• Introduction .
• Definition .
• Techniques available :-
1.CDR grafting .
2.Phage display technologies.
3.Transgenic animals.
Immunotherapeutics in clinical practice
• References
Introductionto Humanisation
In 1975 Kohler and Milstein used hybridoma technology to produce Monoclonal Antibodies
(mAbs) in therapy.
• These mAbs were derived from mice.
• Humans who were treated with these mAbs developed immunogenicity and a peculiar response called Humans
anti-mouse antibody (HAMA).
• After that incident Chimeric mAbs were developed to overcome the potential of patients developing
immunogenicity and triggering an anti-globulin or HAMA response to the rodent derivedmAbs.
• Although chimeric mAbs decreased the probability of triggering HAMA responses and reduced
immunogenicity in patients, the problems were not overcome. Thus the requirement to develop more
‘humanized’ mAbs increased.
Humanisation :
• Humanised mAbs consist of mouse derived ‘complementary determining
regions’ (CDR) which are bound to a human IgG framework.
• Humanised mAbs contain 5-10% of mouse proteins unlike chimeric mAbs
which contains approximately 34% murine protein.
• Humanized mAbs decrease the immunogenicity and anti-globulin
responses even when administered repeatedly and during long term usage
in therapy.
• Humanized mAbs are ideally employed as part of a therapeutic regime
against diseases such as Cancers e.g. Non-Hodgkin’s Lymphoma (NHL),
breast cancer and renal cell carcinoma.
• Humanization is a process by which xenogeneic antibody sequences are modified to reduce
the immunogenicity.
• Here, antibodies are from non-human species whose protein sequences have been modified
to increase their similarity to antibody variants produced naturally in humans.
• The process of "humanization" is usually applied to monoclonal antibodies developed for
administration to humans (for example, antibodies developed as anti-cancer drugs).
• The INTERNATIONAL NON PROPRIETARY NAMES of humanized antibodies end in -zumab, as
in omalizumab.
Structure of antibody
Fab region or
Fc region or
Antigen binding site
• The heavy and light chains that make up
each arm of the antibody are composed of
two regions, called constant (C)
and variable (V).
• These regions are distinguished on the
basis of amino acid similarity—that is,
constant regions have essentially the same
amino acid sequence in all antibody
molecules of the same class (IgG, IgM, IgA,
IgD, or IgE), but the amino acid sequences
of the variable regions differ quite a lot
from antibody to antibody.
• This makes sense, because the variable
regions determine the unique shape of the
antibody-binding site. The tail of the
molecule, which does not bind to antigens,
is composed entirely of the constant
regions of heavy chains.
Humanized antibodies contain murine-sequence derived CDR regions that have been
engrafted .
Techniques of humanizing a mAb :
1.CDR grafting .
2.Phage display technologies.
3.Transgenic animals.
• The complementarity determining regions (CDRs)
are part of the variable ‘ends’ of an antibody which
are responsible for that very antibody to bind to a
specific antigen.
• CDR grafting is a humanization technique whereby
humanized antibody sequences are generated by
carefully selecting the CDRs of the parental
antibody and grafting them into a human
framework (typically murine/Mice origin), but
increasingly other species are being humanized,
including rabbits).
Complementarity-determining regions (CDRs)
are part of the variable chains
in IgS (antibodies) where these molecules bind
to their specific antigen
Variable
region
1) CDR grafting :
2) Phage display technologies :
• Originally described by George P. Smith in 1985.
• Generating antibodies by phage display is based on the process of genetically engineering
bacteriophage and repeated rounds of antigen-guided selection.
• In 2002 Adalimumab (HUMIRA®) was the first therapeutic antibody generated by phage display
technology to be approved for therapeutic. It is also regarded as the world’s first fully human
therapeutic antibody.
Steps involved :
1. The technology involves the introduction of exogenous peptide sequences into a
location in the genome of the phage capsid proteins.
2. The encoded peptides are expressed or "displayed" on the phage surface as a fusion
product with one of the phage coat proteins.
3. This way, instead of having to genetically engineer different proteins or peptides one
at a time and then express, purify, and analyze each variant, phage display libraries
containing up to 1010 variants can be constructed simultaneously.
• Generated by targeted modification of the endogenous mouse antibody genes to
suppress their expression combined with introduction of human antibody heavy and light
chain gene sequences. The result is a mouse which expresses fully human antibodies.
• The first human antibody from a transgenic source was approved in 2006 (Panitumumab)
and since 2009 there have been a further seven including the 2014 approval of Nivolumab
for treatment of melanoma and squamous cell carcinoma.
3) Transgenic mice :
ans
Immunotherapeutics in clinical
practice :
 Monoclonal Antibodies
 Cytokines
 Cancer Vaccines
 Cell-Based Immunotherapy
• The mAbs are artificial versions of large proteins produced by a particular B-cell clone, which have
unique antigen specificity that allows them to bind to epitopes on the cancer cell or in its plasma.
• mAbs are typically of the immunoglobulin G class .
• An mAb can be “naked,” meaning it is not combined with any other drug, or conjugated are joined
with chemotherapy drugs, radioactive particles, or toxins so that they can act as a tool to lead these
agents into cancer cells.
• The primary mechanisms of action for most naked mAbs are antibody-dependent cell-mediated
cytotoxicity (ADCC) and complement-dependent ,triggering direct cell death or blocking prosurvival
signaling, angiogenesis, or immune checkpoints .
• The Food and Drug Administration (FDA) has approved many therapeutic mAbs to treat different
types of cancers.
• In 1997, rituximab (Rituxan, Genentech) became the first mAb approved for clinical use,
indicated in patients with B-cell malignancies.
• Numerous other mAbs have been approved since then, among them
o Trastuzumab (Herceptin, Genentech),
o Alemtuzumab (Campath, Genzyme),
o Ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals),
o Cetuximab (Erbitux, Lilly),
o Bevacizumab (Avastin, Genentech),
o Panitumumab (Vectibix, Amgen),
o Ofatumumab (Arzerra, Novartis),
o Ipilimumab (Yervoy, Bristol-Myers Squibb),
o Brentuximab vedotin (Adcetris, Seattle Genetics),
 Rather than being directed at destroying tumor cells, as is the case with
chemotherapy and radiation treatments, they target the immunosuppression
induced by the cancer.
 Tumors can exploit immunosuppressive checkpoints to impede T-cell activity and
evade the body’s immune system.
 ICBs overcome this mechanism by blocking the checkpoint receptors on T cells
that act as brakes to the immune response; this results in prolonged antitumor
responses.
 Checkpoint ligand/receptor interactions can be stopped by immunomodulatory
mAbs that block IC receptors, such as cytotoxic T-lymphocyte associated antigen 4
(CTLA-4) and PD-1, or immune checkpoint (IC) ligands, such as PD-L1.
• In 2011, the FDA approved the anti–CTLA-4 ICB ipilimumab for the treatment of melanoma,
marking the beginning of the new era for cancer immunotherapy.
• The PD-1 blockers pembrolizumab and nivolumab were granted accelerated approval by the
FDA in September and December 2014, respectively, for patients with unresectable or
metastatic malignant melanoma.
CTLA-4 Blockade :
• CTLA-4, the first IC receptor to be clinically targeted, is expressed exclusively on the surface of T
cells, where its main function is to regulate the amplitude of early-stage T-cell activation.
• The ligands CD80 and CD86 bind to CD28 antigen expressed on T cells, promoting T-cell
activation by amplifying signals from the T-cell receptor (TCR) .
• CTLA-4 is thought to activate the phosphatases SHP2 and PP2A, which counteract the
phosphorylation cascade initiated by the TCR and CD28 activation, ultimately attenuating T-cell
activation.
• Activation of CTLA-4 also enhances the suppressive action of regulatory t-cells (Tregs while
decreasing IL-2 production and IL-2 receptor expression.
PD-1 Blockade :
• The PD-1 receptor present on activated T cells has also emerged as a promising immunotherapy target.
• The binding of PD-1 to its ligands, PD-L1 or PD-L2 (ligands), on CD8 T cells leads to apoptosis, as well as
decreased T-cell proliferation and cytokine production.
• The main role of PD-1 is to limit T-cell activity in peripheral tissues in order to prevent autoimmunity
during an inflammatory response to infection.
• PD-L1 and PD-L2 are also overexpressed on cancer cells and in the tumor
microenvironment. Consequently, PD-L1 expression is described in many cancer types, including solid
tumors.
• It is also expressed on a large proportion of TILs from many different tumor types—a finding that
correlates with low cytokine production resulting in reduced antitumor activity.
• Cytokines, such as
• interferons,
• interleukins,
• lymphokines,
• monokines,
• chemokines, and growth factors,
are immune modulators that are produced naturally by numerous cell types.
• They are small-protein molecules that have variable activities—most importantly, regulation of immunity and
inflammation.
• These messenger molecules, which are secreted by cells of the immune system (such as lymphocytes,
monocytes, and macrophages), regulate leukocyte differentiation, migration, activation, and suppression.
• Certain cytokines can directly enhance or suppress T-cell response against cancer cells, so it is not surprising
that the systemic administration of cytokines (initially interferons and interleukins) was among the first
approaches to cancer immunotherapy
• It is an immunostimulant that uses several well-characterized molecular mechanisms to mediate its effects.
• Its enhancement of dendritic cell (DC) activation and maturation improves anti-tumor immunity by
enhancing antigen presentation to immune cells.
• In addition, IFN-α promotes a Th1 immune response, increasing the activity of CTLs involved in tumor cell
lysis, and it also enhances the cytotoxic activities of NK cells.
• IFN-α activity also directly targets tumor cell growth and oncogene expression.
• IFN-α was the first cytokine produced with recombinant technology.1986, it was approved for the
treatment of hairy cell leukemia, and an indication for chronic myelogenous leukemia was added later.
• Of the numerous IFN subtypes, IFN-α, specifically IFN-α2b, is the one used most widely in cancer
immunotherapy
• Interleukins are predominantly secreted by CD4+ helper T-cell subsets that are involved in the development,
activation, and suppression of CD8+ cytotoxic T cells, macrophages, and NK cells.
• Of all the interleukins, IL-2 has been the most thoroughly studied, with recombinant IL-2 (rhIL-2) being the most
broadly used agent in cancer immunotherapy strategies.
• IL-2 is a critical cofactor that activates cytotoxic tumour infiltrating leukocytes (TILs); enhances the antitumor
activity of NK cells; induces lymphokine-activated killer cells that mediate antitumor effects; and promotes the
growth and proliferation of Tregs.
• In 1992 rhIL-2 (aldesleukin [Proleukin, Prometheus Laboratories]) received approval for the treatment of RCC,
and in 1998, an indication was added for metastatic melanoma.
• The use of a vaccine to encourage the body to develop antibodies that target peptides or antigens that are
present on the tumor.
• Proper T-cell responses against these cancer antigens can, however, be compromised by low T-cell affinity
to self-antigens .
• Immune system impairment due to immunosuppressive therapy.
• Tumor -induced immune response inhibition due to secretion of cytokines (IL-10, transforming growth
factor-beta);
• Or manipulation of immune cells through immunosuppressive factors (e.g., Tregs, tumor-associated
macrophages, and myeloid-derived suppressor cells)
hypochlorous acid-oxidized ovarian cancer lysate (HOCL) Dendritic cell (DC)
• One goal of cancer vaccines is to stimulate the immune system to attack and
eradicate cancer cells.
• To this end, cancer vaccines contain
• whole cancer cells,
• parts of cancer cells,
• or purified antigens that enhance the immune response against cancer cells.
• Tumor vaccines can be
• peptide-based,
• immune cell-
• or DC-based,
• or tumor cell-based, each offering unique advantages and disadvantages.
• Oncolytic virus, nanocarrier, and DNA-based vaccines are also being investigated.
• Peptide-based vaccines elicit an immune response against a single tumor antigen
expressed in association with HLA molecules on the surface of tumor cells.
• These vaccines are less likely to produce toxicity in normal cells and tissues; however,
they have limitations with respect to the need to properly identify the tumor antigen
peptide and patient HLA type .
DCs are specialized antigen-presenting cells that play a major role in capturing, processing, and
presenting tumor antigens to T cells and eliciting an immune response.
Among the earliest cancer vaccine approaches was the use of monocyte-derived DCs grown ex vivo,
pulsed with purified TAAs or autologous tumor cell lysates.
Sipuleucel-T (Provenge, Dendreon Corp.), the FDA-approved first-in-class DC-based cancer vaccine,
represented a milestone for cancer immunotherapy when it was approved in 2010 for the
treatment of castration-resistant prostate cancer.
Second-generation DC-based vaccines use innovative in vitro culturing techniques with media
enriched with critical cytokines, enhancing immunogenicity and improving DC function
• Tumor-cell–based vaccines use whole tumor cells to provide a source
of immunogenic material.
• Unlike peptide-based vaccines, they can be used to present a broad
range of epitopes to the immune system to mount a defense.
• These vaccines can be autologous, using tumor cells from the vaccine
recipient, or allogeneic, using tumor cells from another patient.
• Once the tumor cells are obtained, they can be prepared for
immunization by irradiation.They are then administered either alone
or in combination with an adjuvant such as granulocyte macrophage
colony-stimulating factor.
• Tumor-cell–based vaccines such as M-Vax (AVAX Technologies) have
demonstrated efficacy in targeting RCC, melanoma, and acute myeloid
leukemia in clinical trials.8
Rather than provoking an immune response, cell-based
immunotherapies, such as adoptive T-cell therapy, contain intrinsic
antitumor properties.
Adoptive T-cell therapy is the transfer of natural or genetically
modified T cells that have been expanded ex vivo into patients to treat
metastatic cancers.
The infused cells can be allogenic or autologous.
After the infusion, an immune response is elicited based on allogeneic
differences in the expression of peptide/HLA complexes or minor
histocompatibility antigens.
Cell-based immunotherapy treatments with infusions of genetically
modified autologous or allogeneic T cells have also demonstrated
impressive antitumor activity in some hematologic malignancies.
This method is based on the identification of all mutated
genes through exome sequencing of tumor samples.
Then, the amino-acid sequences present around the
mutation sites are entered into prediction software to
identify all potential epitopes.
These peptide sequences are used for ex vivo expansion of
tumour infiltrating lymphocyte (TIL) that are targeted with
known specificity.
1. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-
vaccines/understanding-immunotherapy
2. https://www.fusionantibodies.com/blog/2016/january/ebr-antibody-humanization-article.
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190434/.
4. https://www.clinicaloptions.com/oncology/programs/immunotherapy-in-cancer/cco-
slideset/immunotherapy_slides.
5)http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572005000100001
6) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011222/
7) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440098/
References :

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Humanisation of antibodies & immunotherapeutics in clinical practice

  • 1. Humanisation . Immunotherapeutics in clinical practice . Presented by Aquib Naseer M Pharm Pharmacology School of Pharmaceutical Edu & Research, Jamia Hamdard
  • 2. Contents : Humanization : • Introduction . • Definition . • Techniques available :- 1.CDR grafting . 2.Phage display technologies. 3.Transgenic animals. Immunotherapeutics in clinical practice • References
  • 4. In 1975 Kohler and Milstein used hybridoma technology to produce Monoclonal Antibodies (mAbs) in therapy. • These mAbs were derived from mice. • Humans who were treated with these mAbs developed immunogenicity and a peculiar response called Humans anti-mouse antibody (HAMA). • After that incident Chimeric mAbs were developed to overcome the potential of patients developing immunogenicity and triggering an anti-globulin or HAMA response to the rodent derivedmAbs. • Although chimeric mAbs decreased the probability of triggering HAMA responses and reduced immunogenicity in patients, the problems were not overcome. Thus the requirement to develop more ‘humanized’ mAbs increased. Humanisation :
  • 5. • Humanised mAbs consist of mouse derived ‘complementary determining regions’ (CDR) which are bound to a human IgG framework. • Humanised mAbs contain 5-10% of mouse proteins unlike chimeric mAbs which contains approximately 34% murine protein. • Humanized mAbs decrease the immunogenicity and anti-globulin responses even when administered repeatedly and during long term usage in therapy. • Humanized mAbs are ideally employed as part of a therapeutic regime against diseases such as Cancers e.g. Non-Hodgkin’s Lymphoma (NHL), breast cancer and renal cell carcinoma.
  • 6. • Humanization is a process by which xenogeneic antibody sequences are modified to reduce the immunogenicity. • Here, antibodies are from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. • The process of "humanization" is usually applied to monoclonal antibodies developed for administration to humans (for example, antibodies developed as anti-cancer drugs). • The INTERNATIONAL NON PROPRIETARY NAMES of humanized antibodies end in -zumab, as in omalizumab.
  • 7. Structure of antibody Fab region or Fc region or Antigen binding site
  • 8. • The heavy and light chains that make up each arm of the antibody are composed of two regions, called constant (C) and variable (V). • These regions are distinguished on the basis of amino acid similarity—that is, constant regions have essentially the same amino acid sequence in all antibody molecules of the same class (IgG, IgM, IgA, IgD, or IgE), but the amino acid sequences of the variable regions differ quite a lot from antibody to antibody. • This makes sense, because the variable regions determine the unique shape of the antibody-binding site. The tail of the molecule, which does not bind to antigens, is composed entirely of the constant regions of heavy chains.
  • 9. Humanized antibodies contain murine-sequence derived CDR regions that have been engrafted .
  • 10. Techniques of humanizing a mAb : 1.CDR grafting . 2.Phage display technologies. 3.Transgenic animals.
  • 11. • The complementarity determining regions (CDRs) are part of the variable ‘ends’ of an antibody which are responsible for that very antibody to bind to a specific antigen. • CDR grafting is a humanization technique whereby humanized antibody sequences are generated by carefully selecting the CDRs of the parental antibody and grafting them into a human framework (typically murine/Mice origin), but increasingly other species are being humanized, including rabbits). Complementarity-determining regions (CDRs) are part of the variable chains in IgS (antibodies) where these molecules bind to their specific antigen Variable region 1) CDR grafting :
  • 12. 2) Phage display technologies : • Originally described by George P. Smith in 1985. • Generating antibodies by phage display is based on the process of genetically engineering bacteriophage and repeated rounds of antigen-guided selection. • In 2002 Adalimumab (HUMIRA®) was the first therapeutic antibody generated by phage display technology to be approved for therapeutic. It is also regarded as the world’s first fully human therapeutic antibody.
  • 13. Steps involved : 1. The technology involves the introduction of exogenous peptide sequences into a location in the genome of the phage capsid proteins. 2. The encoded peptides are expressed or "displayed" on the phage surface as a fusion product with one of the phage coat proteins. 3. This way, instead of having to genetically engineer different proteins or peptides one at a time and then express, purify, and analyze each variant, phage display libraries containing up to 1010 variants can be constructed simultaneously.
  • 14. • Generated by targeted modification of the endogenous mouse antibody genes to suppress their expression combined with introduction of human antibody heavy and light chain gene sequences. The result is a mouse which expresses fully human antibodies. • The first human antibody from a transgenic source was approved in 2006 (Panitumumab) and since 2009 there have been a further seven including the 2014 approval of Nivolumab for treatment of melanoma and squamous cell carcinoma. 3) Transgenic mice :
  • 15. ans
  • 16. Immunotherapeutics in clinical practice :  Monoclonal Antibodies  Cytokines  Cancer Vaccines  Cell-Based Immunotherapy
  • 17.
  • 18. • The mAbs are artificial versions of large proteins produced by a particular B-cell clone, which have unique antigen specificity that allows them to bind to epitopes on the cancer cell or in its plasma. • mAbs are typically of the immunoglobulin G class . • An mAb can be “naked,” meaning it is not combined with any other drug, or conjugated are joined with chemotherapy drugs, radioactive particles, or toxins so that they can act as a tool to lead these agents into cancer cells. • The primary mechanisms of action for most naked mAbs are antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent ,triggering direct cell death or blocking prosurvival signaling, angiogenesis, or immune checkpoints .
  • 19.
  • 20. • The Food and Drug Administration (FDA) has approved many therapeutic mAbs to treat different types of cancers. • In 1997, rituximab (Rituxan, Genentech) became the first mAb approved for clinical use, indicated in patients with B-cell malignancies. • Numerous other mAbs have been approved since then, among them o Trastuzumab (Herceptin, Genentech), o Alemtuzumab (Campath, Genzyme), o Ibritumomab tiuxetan (Zevalin, Spectrum Pharmaceuticals), o Cetuximab (Erbitux, Lilly), o Bevacizumab (Avastin, Genentech), o Panitumumab (Vectibix, Amgen), o Ofatumumab (Arzerra, Novartis), o Ipilimumab (Yervoy, Bristol-Myers Squibb), o Brentuximab vedotin (Adcetris, Seattle Genetics),
  • 21.  Rather than being directed at destroying tumor cells, as is the case with chemotherapy and radiation treatments, they target the immunosuppression induced by the cancer.  Tumors can exploit immunosuppressive checkpoints to impede T-cell activity and evade the body’s immune system.  ICBs overcome this mechanism by blocking the checkpoint receptors on T cells that act as brakes to the immune response; this results in prolonged antitumor responses.  Checkpoint ligand/receptor interactions can be stopped by immunomodulatory mAbs that block IC receptors, such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and PD-1, or immune checkpoint (IC) ligands, such as PD-L1.
  • 22.
  • 23. • In 2011, the FDA approved the anti–CTLA-4 ICB ipilimumab for the treatment of melanoma, marking the beginning of the new era for cancer immunotherapy. • The PD-1 blockers pembrolizumab and nivolumab were granted accelerated approval by the FDA in September and December 2014, respectively, for patients with unresectable or metastatic malignant melanoma.
  • 24.
  • 25. CTLA-4 Blockade : • CTLA-4, the first IC receptor to be clinically targeted, is expressed exclusively on the surface of T cells, where its main function is to regulate the amplitude of early-stage T-cell activation. • The ligands CD80 and CD86 bind to CD28 antigen expressed on T cells, promoting T-cell activation by amplifying signals from the T-cell receptor (TCR) . • CTLA-4 is thought to activate the phosphatases SHP2 and PP2A, which counteract the phosphorylation cascade initiated by the TCR and CD28 activation, ultimately attenuating T-cell activation. • Activation of CTLA-4 also enhances the suppressive action of regulatory t-cells (Tregs while decreasing IL-2 production and IL-2 receptor expression.
  • 26.
  • 27. PD-1 Blockade : • The PD-1 receptor present on activated T cells has also emerged as a promising immunotherapy target. • The binding of PD-1 to its ligands, PD-L1 or PD-L2 (ligands), on CD8 T cells leads to apoptosis, as well as decreased T-cell proliferation and cytokine production. • The main role of PD-1 is to limit T-cell activity in peripheral tissues in order to prevent autoimmunity during an inflammatory response to infection. • PD-L1 and PD-L2 are also overexpressed on cancer cells and in the tumor microenvironment. Consequently, PD-L1 expression is described in many cancer types, including solid tumors. • It is also expressed on a large proportion of TILs from many different tumor types—a finding that correlates with low cytokine production resulting in reduced antitumor activity.
  • 28.
  • 29. • Cytokines, such as • interferons, • interleukins, • lymphokines, • monokines, • chemokines, and growth factors, are immune modulators that are produced naturally by numerous cell types. • They are small-protein molecules that have variable activities—most importantly, regulation of immunity and inflammation. • These messenger molecules, which are secreted by cells of the immune system (such as lymphocytes, monocytes, and macrophages), regulate leukocyte differentiation, migration, activation, and suppression. • Certain cytokines can directly enhance or suppress T-cell response against cancer cells, so it is not surprising that the systemic administration of cytokines (initially interferons and interleukins) was among the first approaches to cancer immunotherapy
  • 30.
  • 31. • It is an immunostimulant that uses several well-characterized molecular mechanisms to mediate its effects. • Its enhancement of dendritic cell (DC) activation and maturation improves anti-tumor immunity by enhancing antigen presentation to immune cells. • In addition, IFN-α promotes a Th1 immune response, increasing the activity of CTLs involved in tumor cell lysis, and it also enhances the cytotoxic activities of NK cells. • IFN-α activity also directly targets tumor cell growth and oncogene expression. • IFN-α was the first cytokine produced with recombinant technology.1986, it was approved for the treatment of hairy cell leukemia, and an indication for chronic myelogenous leukemia was added later. • Of the numerous IFN subtypes, IFN-α, specifically IFN-α2b, is the one used most widely in cancer immunotherapy
  • 32.
  • 33. • Interleukins are predominantly secreted by CD4+ helper T-cell subsets that are involved in the development, activation, and suppression of CD8+ cytotoxic T cells, macrophages, and NK cells. • Of all the interleukins, IL-2 has been the most thoroughly studied, with recombinant IL-2 (rhIL-2) being the most broadly used agent in cancer immunotherapy strategies. • IL-2 is a critical cofactor that activates cytotoxic tumour infiltrating leukocytes (TILs); enhances the antitumor activity of NK cells; induces lymphokine-activated killer cells that mediate antitumor effects; and promotes the growth and proliferation of Tregs. • In 1992 rhIL-2 (aldesleukin [Proleukin, Prometheus Laboratories]) received approval for the treatment of RCC, and in 1998, an indication was added for metastatic melanoma.
  • 34.
  • 35. • The use of a vaccine to encourage the body to develop antibodies that target peptides or antigens that are present on the tumor. • Proper T-cell responses against these cancer antigens can, however, be compromised by low T-cell affinity to self-antigens . • Immune system impairment due to immunosuppressive therapy. • Tumor -induced immune response inhibition due to secretion of cytokines (IL-10, transforming growth factor-beta); • Or manipulation of immune cells through immunosuppressive factors (e.g., Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells)
  • 36. hypochlorous acid-oxidized ovarian cancer lysate (HOCL) Dendritic cell (DC)
  • 37. • One goal of cancer vaccines is to stimulate the immune system to attack and eradicate cancer cells. • To this end, cancer vaccines contain • whole cancer cells, • parts of cancer cells, • or purified antigens that enhance the immune response against cancer cells. • Tumor vaccines can be • peptide-based, • immune cell- • or DC-based, • or tumor cell-based, each offering unique advantages and disadvantages. • Oncolytic virus, nanocarrier, and DNA-based vaccines are also being investigated.
  • 38. • Peptide-based vaccines elicit an immune response against a single tumor antigen expressed in association with HLA molecules on the surface of tumor cells. • These vaccines are less likely to produce toxicity in normal cells and tissues; however, they have limitations with respect to the need to properly identify the tumor antigen peptide and patient HLA type .
  • 39.
  • 40. DCs are specialized antigen-presenting cells that play a major role in capturing, processing, and presenting tumor antigens to T cells and eliciting an immune response. Among the earliest cancer vaccine approaches was the use of monocyte-derived DCs grown ex vivo, pulsed with purified TAAs or autologous tumor cell lysates. Sipuleucel-T (Provenge, Dendreon Corp.), the FDA-approved first-in-class DC-based cancer vaccine, represented a milestone for cancer immunotherapy when it was approved in 2010 for the treatment of castration-resistant prostate cancer. Second-generation DC-based vaccines use innovative in vitro culturing techniques with media enriched with critical cytokines, enhancing immunogenicity and improving DC function
  • 41.
  • 42. • Tumor-cell–based vaccines use whole tumor cells to provide a source of immunogenic material. • Unlike peptide-based vaccines, they can be used to present a broad range of epitopes to the immune system to mount a defense. • These vaccines can be autologous, using tumor cells from the vaccine recipient, or allogeneic, using tumor cells from another patient. • Once the tumor cells are obtained, they can be prepared for immunization by irradiation.They are then administered either alone or in combination with an adjuvant such as granulocyte macrophage colony-stimulating factor. • Tumor-cell–based vaccines such as M-Vax (AVAX Technologies) have demonstrated efficacy in targeting RCC, melanoma, and acute myeloid leukemia in clinical trials.8
  • 43.
  • 44. Rather than provoking an immune response, cell-based immunotherapies, such as adoptive T-cell therapy, contain intrinsic antitumor properties. Adoptive T-cell therapy is the transfer of natural or genetically modified T cells that have been expanded ex vivo into patients to treat metastatic cancers. The infused cells can be allogenic or autologous. After the infusion, an immune response is elicited based on allogeneic differences in the expression of peptide/HLA complexes or minor histocompatibility antigens. Cell-based immunotherapy treatments with infusions of genetically modified autologous or allogeneic T cells have also demonstrated impressive antitumor activity in some hematologic malignancies.
  • 45. This method is based on the identification of all mutated genes through exome sequencing of tumor samples. Then, the amino-acid sequences present around the mutation sites are entered into prediction software to identify all potential epitopes. These peptide sequences are used for ex vivo expansion of tumour infiltrating lymphocyte (TIL) that are targeted with known specificity.
  • 46. 1. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and- vaccines/understanding-immunotherapy 2. https://www.fusionantibodies.com/blog/2016/january/ebr-antibody-humanization-article. 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190434/. 4. https://www.clinicaloptions.com/oncology/programs/immunotherapy-in-cancer/cco- slideset/immunotherapy_slides. 5)http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1415-47572005000100001 6) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011222/ 7) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440098/ References :